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Sample records for primary immunodeficiencies pid

  1. The German national registry for primary immunodeficiencies (PID)

    PubMed Central

    Gathmann, B; Goldacker, S; Klima, M; Belohradsky, B H; Notheis, G; Ehl, S; Ritterbusch, H; Baumann, U; Meyer-Bahlburg, A; Witte, T; Schmidt, R; Borte, M; Borte, S; Linde, R; Schubert, R; Bienemann, K; Laws, H-J; Dueckers, G; Roesler, J; Rothoeft, T; Krüger, R; Scharbatke, E C; Masjosthusmann, K; Wasmuth, J-C; Moser, O; Kaiser, P; Groß-Wieltsch, U; Classen, C F; Horneff, G; Reiser, V; Binder, N; El-Helou, S M; Klein, C; Grimbacher, B; Kindle, G

    2013-01-01

    In 2009, a federally funded clinical and research consortium (PID–NET, http://www.pid-net.org) established the first national registry for primary immunodeficiencies (PID) in Germany. The registry contains clinical and genetic information on PID patients and is set up within the framework of the existing European Database for Primary Immunodeficiencies, run by the European Society for Primary Immunodeficiencies. Following the example of other national registries, a central data entry clerk has been employed to support data entry at the participating centres. Regulations for ethics approvals have presented a major challenge for participation of individual centres and have led to a delay in data entry in some cases. Data on 630 patients, entered into the European registry between 2004 and 2009, were incorporated into the national registry. From April 2009 to March 2012, the number of contributing centres increased from seven to 21 and 738 additional patients were reported, leading to a total number of 1368 patients, of whom 1232 were alive. The age distribution of living patients differs significantly by gender, with twice as many males than females among children, but 15% more women than men in the age group 30 years and older. The diagnostic delay between onset of symptoms and diagnosis has decreased for some PID over the past 20 years, but remains particularly high at a median of 4 years in common variable immunodeficiency (CVID), the most prevalent PID. PMID:23607573

  2. Primary immunodeficiency

    PubMed Central

    2011-01-01

    Primary immunodeficiency disorder (PID) refers to a heterogeneous group of over 130 disorders that result from defects in immune system development and/or function. PIDs are broadly classified as disorders of adaptive immunity (i.e., T-cell, B-cell or combined immunodeficiencies) or of innate immunity (e.g., phagocyte and complement disorders). Although the clinical manifestations of PIDs are highly variable, most disorders involve at least an increased susceptibility to infection. Early diagnosis and treatment are imperative for preventing significant disease-associated morbidity and, therefore, consultation with a clinical immunologist is essential. PIDs should be suspected in patients with: recurrent sinus or ear infections or pneumonias within a 1 year period; failure to thrive; poor response to prolonged use of antibiotics; persistent thrush or skin abscesses; or a family history of PID. Patients with multiple autoimmune diseases should also be evaluated. Diagnostic testing often involves lymphocyte proliferation assays, flow cytometry, measurement of serum immunoglobulin (Ig) levels, assessment of serum specific antibody titers in response to vaccine antigens, neutrophil function assays, stimulation assays for cytokine responses, and complement studies. The treatment of PIDs is complex and generally requires both supportive and definitive strategies. Ig replacement therapy is the mainstay of therapy for B-cell disorders, and is also an important supportive treatment for many patients with combined immunodeficiency disorders. The heterogeneous group of disorders involving the T-cell arm of the adaptive system, such as severe combined immunodeficiency (SCID), require immune reconstitution as soon as possible. The treatment of innate immunodeficiency disorders varies depending on the type of defect, but may involve antifungal and antibiotic prophylaxis, cytokine replacement, vaccinations and bone marrow transplantation. This article provides a detailed overview

  3. [Basics of primary immunodeficiencies].

    PubMed

    Hernández-Martínez, Claudia; Espinosa-Rosales, Francisco; Espinosa-Padilla, Sara Elva; Hernández-Martínez, Ana Rosa; Blancas-Galicia, Lizbeth

    2016-01-01

    Primary immunodeficiencies (PID) are a heterogeneous group of inherited disorders, the etiology are the defects in the development or function of the immune system. The principal PID manifestations are the infections in early age, malignancy and diseases of immune dysregulation as autoimmunity and allergy. PIDs are genetics disorders and most of them are inherited as autosomal recessive, also this group of diseases is more prevalent in males and in childhood. The antibody immunodeficiency is the PID more common in adults. The more frequent disorders are the infections in the respiratory tract, abscesses, candidiasis, diarrhea, BCGosis etc. Initial approach included a complete blood count and quantification of immunoglobulins. The delay in diagnosis could be explained due to a perception that the recurrent infections are normal process or think that they are exclusively of childhood. The early diagnosis of PID by primary care physicians is important to opportune treatment and better prognosis. PMID:27174761

  4. Current Perspectives on Primary Immunodeficiency Diseases

    PubMed Central

    Kumar, Arvind; Teuber, Suzanne S.; Gershwin, M. Eric

    2006-01-01

    Since the original description of X-linked agammaglobulinemia in 1952, the number of independent primary immunodeficiency diseases (PIDs) has expanded to more than 100 entities. By definition, a PID is a genetically determined disorder resulting in enhanced susceptibility to infectious disease. Despite the heritable nature of these diseases, some PIDs are clinically manifested only after prerequisite environmental exposures but they often have associated malignant, allergic, or autoimmune manifestations. PIDs must be distinguished from secondary or acquired immunodeficiencies, which are far more common. In this review, we will place these immunodeficiencies in the context of both clinical and laboratory presentations as well as highlight the known genetic basis. PMID:17162365

  5. Autoimmunity in primary T-cell immunodeficiencies.

    PubMed

    Azizi, Gholamreza; Ghanavatinejad, Alireza; Abolhassani, Hassan; Yazdani, Reza; Rezaei, Nima; Mirshafiey, Abbas; Aghamohammadi, Asghar

    2016-09-01

    Primary immunodeficiency diseases (PID) are a genetically heterogeneous group of more than 270 disorders that affect distinct components of both humoral and cellular arms of the immune system. Primary T cell immunodeficiencies affect subjects at the early age of life. In most cases, T-cell PIDs become apparent as combined T- and B-cell deficiencies. Patients with T-cell PID are prone to life-threatening infections. On the other hand, non-infectious complications such as lymphoproliferative diseases, cancers and autoimmunity seem to be associated with the primary T-cell immunodeficiencies. Autoimmune disorders of all kinds (organ specific or systemic ones) could be subjected to this class of PIDs; however, the most frequent autoimmune disorders are immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA). In this review, we discuss the proposed mechanisms of autoimmunity and review the literature reported on autoimmune disorder in each type of primary T-cell immunodeficiencies. PMID:27063703

  6. [Understanding primary immunodeficiencies: usefulness of a register].

    PubMed

    Jandus, Peter; Grange, Elliot; Seebach, Jörg D

    2016-04-01

    Primary Immunodeficiency Diseases (PID) comprise inborn defects of the immune system which are and therefore difficult to study For this reason, the European Society for ImmunoDeficiencies (ESID) has set up an internet-based international patient and research database which integrates research data with more detailed clinical information. These disorders are not only found in children, but also in adults resulting in a wide range of clinical manifestations. Primary immunodeficiency adults are much less known and may remain undiagnosed. PMID:27197327

  7. Gene therapy for primary immunodeficiencies.

    PubMed

    Fischer, A; Hacein-Bey Abina, S; Touzot, F; Cavazzana, M

    2015-12-01

    Gene therapy has effectively entered Medicine via the field of primary immunodeficiencies (PID). Because hematopoietic stem cells are accessible and because it was understood that genetic correction of lymphocyte progenitor cells carrying a genetic defect impairing differentiation, could result in the production of long-lived T lymphocytes, it was reasoned that ex vivo gene transfer in hematopoietic cells could lead to disease phenotype correction. Retroviral vectors were designed to ex vivo transduce such cells. This has indeed been shown to lead to sustained correction of the T cell immunodeficiency associated with two forms of severe combined immunodeficiencies (SCID) for now more than ten years. Occurrence in some patients of genotoxicity related to retroviral vectors integration close to and transactivation of oncogenes has led to the development of retroviral vectors devoid of its enhancer element. Results of recent trials performed for several forms of PID indeed suggest that their use is both safe and efficacious. It is thus anticipated that their application to the treatment of many more life threatening PID will be developed over the coming years. PMID:25708106

  8. [Innate immunity primary immunodeficiencies and infections].

    PubMed

    Duchamp, M; Miot, C; Bustamante, J C; Picard, C

    2016-07-01

    The diagnosis of primary immunodeficiency diseases (PIDs) is important for the early and adaptive care of patients and their families. Among the various known PIDs, a number of them concern the innate immune system, which involve a set of cells and mechanisms involved in the host defense by a nonspecific and fast response. The majority of patients with innate immunity defects have a predisposition to one isolated type of infection (bacterial, viral, or fungal), dependent on the genetic defect involved. This article describes the different PIDs involving innate immunity and the immunological investigations allowing for their diagnosis. PMID:27266636

  9. Family Physician Perspectives on Primary Immunodeficiency Diseases

    PubMed Central

    Orange, Jordan S.; Seeborg, Filiz O.; Boyle, Marcia; Scalchunes, Christopher; Hernandez-Trujillo, Vivian

    2016-01-01

    Primary immunodeficiency diseases (PIDs) include over 250 diverse disorders. The current study assessed management of PID by family practice physicians. The American Academy of Allergy, Asthma, and Immunology Primary Immunodeficiency Committee and the Immune Deficiency Foundation conducted an incentivized mail survey of family practice physician members of the American Medical Association and the American Osteopathic Association in direct patient care. Responses were compared with subspecialist immunologist responses from a similar survey. Surveys were returned by 528 (of 4500 surveys mailed) family practice physicians, of whom 44% reported following ≥1 patient with PID. Selective immunoglobulin A deficiency (21%) and chronic granulomatous disease (11%) were most common and were followed by significantly more subspecialist immunologists (P < 0.05). Use of intravenously administered immunoglobulin and live viral vaccinations across PID was significantly different (P < 0.05). Few family practice physicians were aware of professional guidelines for diagnosis and management of PID (4 vs. 79% of subspecialist immunologists, P < 0.05). Family practice physicians will likely encounter patients with PID diagnoses during their career. Differences in how family practice physicians and subspecialist immunologists manage patients with PID underscore areas where improved educational and training initiatives may benefit patient care. PMID:27066486

  10. Family Physician Perspectives on Primary Immunodeficiency Diseases.

    PubMed

    Orange, Jordan S; Seeborg, Filiz O; Boyle, Marcia; Scalchunes, Christopher; Hernandez-Trujillo, Vivian

    2016-01-01

    Primary immunodeficiency diseases (PIDs) include over 250 diverse disorders. The current study assessed management of PID by family practice physicians. The American Academy of Allergy, Asthma, and Immunology Primary Immunodeficiency Committee and the Immune Deficiency Foundation conducted an incentivized mail survey of family practice physician members of the American Medical Association and the American Osteopathic Association in direct patient care. Responses were compared with subspecialist immunologist responses from a similar survey. Surveys were returned by 528 (of 4500 surveys mailed) family practice physicians, of whom 44% reported following ≥1 patient with PID. Selective immunoglobulin A deficiency (21%) and chronic granulomatous disease (11%) were most common and were followed by significantly more subspecialist immunologists (P < 0.05). Use of intravenously administered immunoglobulin and live viral vaccinations across PID was significantly different (P < 0.05). Few family practice physicians were aware of professional guidelines for diagnosis and management of PID (4 vs. 79% of subspecialist immunologists, P < 0.05). Family practice physicians will likely encounter patients with PID diagnoses during their career. Differences in how family practice physicians and subspecialist immunologists manage patients with PID underscore areas where improved educational and training initiatives may benefit patient care. PMID:27066486

  11. Rheumatologic manifestations of primary immunodeficiency diseases.

    PubMed

    Dimitriades, V R; Sorensen, R

    2016-04-01

    In the last 5 years, several hundred articles have been published concerning the link between primary immunodeficiency disease (PID) and rheumatologic diseases. Although rheumatologic complications were originally thought to be at the opposite ends of the spectrum of immunopathologic manifestations, they are now all being considered secondary manifestations of a causative primary "immune derangement." For the rheumatologist, it is important to be able to identify patients who may present with typical rheumatologic findings but who have an underlying PID. In a systematic manner, this overview addresses both the systemic and organ-based rheumatologic diseases which have known associations with primary immunodeficiencies, and explores how immunodeficiency may actually cause these clinical manifestations. PMID:26971790

  12. [Molecular diagnosis of primary immunodeficiencies].

    PubMed

    García Rodríguez, M C; López Granados, E; Cambronero Martínez, R; Ferreira Cerdán, A; Fontán Casariego, G

    2001-01-01

    Knowledge of the molecular defects responsible for some primary immunodeficiency diseases (PIDs) offers undoubted advantages in establishing a reliable diagnosis. Such knowledge would allow us not only to establish a prognosis but also to instigate the most appropriate therapy. After molecular diagnosis, some patients could benefit from gene therapy. However, apart from the diagnosis of the disease, molecular biological techniques also enable more reliable identification of carriers and, when suggested by the family history and when the familial defect is already known, prenatal diagnosis will also be possible, thus establishing the earliest possible treatment. Using the single-stranded conformational polymorphism technique followed by direct sequencing, we found 22 different mutations in 22 patients from unrelated families and with a phenotype compatible with x-linked agammaglobulinemia. Fourteen of these are new, previously undescribed mutations and the remaining eight are already included in the data base (http://www.uta.fi/imt/bioinfo/Btkbase). Analysis of the female carrier was performed in all the mothers and the mutation was de novo in only one patient. Study of the BtK gene enabled differential diagnosis with common variable immunodeficiency disease in some patients who showed absent or very low lymphocyte B counts as well as forms of autosomal recessive agammaglobulinemia. Using the same techniques, we were able to identify mutations in the CD40 ligand gene in three families in which one of the members had clinical and biological phenotype compatible with X-linked hyper-IgM. Molecular diagnosis was very useful in identifying carriers in these families as well as in making the differential diagnosis among patients with common variable immunodeficiency disease. Purely on this were we able to provide appropriate genetic counseling. PMID:11434883

  13. Primary Immunodeficiencies with Elevated IgE.

    PubMed

    Mogensen, Trine H

    2016-01-01

    In recent years a number of primary immunodeficiencies (PIDs) characterized by elevated Immunoglobulin E (IgE) levels have been uncovered and termed as Hyper-IgE syndrome (HIES). In addition to the elevated levels of IgE, patients with these PIDs display a spectrum of infections by staphylococci and fungi, and in some cases viruses, particularly affecting skin and lungs. Most of these PIDs also have a non-infectious phenotype, comprising musculoskeletal, vascular, and neurological abnormalities. The genetic basis for the majority of conditions with elevated IgE has now been established and includes mutations in STAT3, DOCK8, TYK2, and most recently PGM3 molecules. However, in some patients with the relevant phenotype, mutations in these molecules are not identified, suggesting additional genetic etiologies of HIES not yet discovered. As the immunological and molecular basis of HIES is being unraveled, important insights are emerging that may have implications for our understanding of basic principles of immunology and protective immunity as well as for the pathogenesis and clinical management of patients with these complex and challenging PIDs. In this review, are presented the current knowledge on the clinical presentation, infectious phenotype, and the genetic and immunological pathogenesis of hyper-IgE syndromes as well as some other PIDs with elevated levels of IgE. PMID:25970001

  14. Neutropenia in primary immunodeficiency

    PubMed Central

    Sokolic, Robert

    2016-01-01

    Purpose of review Neutropenia is a feature of several primary immunodeficiency diseases (PIDDs). Because of the diverse pathophysiologies of the PIDDs and the rarity of each disorder, data are often lacking, leading to the necessity of empiric treatment. Recent developments in the understanding of neutropenia in several of the PIDDs make a review of the data timely. Recent findings The category of severe congenital neutropenia continues to expand. Mutations in G6PC3 have been identified as the cause of neutropenia in a minority of previously molecularly undefined cases. Recent advances have broadened our understanding of the pathophysiology and the clinical expression of this disorder. A possible function of the C16orf57 gene has been hypothesized that may explain the clinical overlap between Clerucuzio-type poikiloderma with neutropenia and other marrow diseases. Plerixafor has been shown to be a potentially useful treatment in the warts, hypogammaglobulinemia, infection, and myelokathexis syndrome. Investigations of patients with adenosine deaminase deficient severe combined immunodeficiency have identified neutropenia, and particularly susceptibility to myelotoxins, as a feature of this disorder. Granulocyte-colony stimulating factor is the treatment of choice for neutropenia in PIDD, whereas hematopoietic cell transplantation is the only curative option. Summary The number of PIDDs associated with neutropenia has increased, as has our understanding of the range of phenotypes. Additional data and hypotheses have been generated helping to explain the diversity of presentations of neutropenia in PIDDs. PMID:23196894

  15. Bacillus Calmette-Guérin (BCG) complications associated with primary immunodeficiency diseases

    PubMed Central

    Norouzi, Sayna; Aghamohammadi, Asghar; Mamishi, Setareh; Rosenzweig, Sergio D.; Rezaei, Nima

    2016-01-01

    Summary Primary immunodeficiency diseases (PIDs) are a group of inherited disorders, characterized by defects of the immune system predisposing individuals to variety of manifestations, including recurrent infections and unusual vaccine complications. There are a number of PIDs prone to Bacillus Calmette-Guérin (BCG) complications. This review presents an update on our understanding about the BCGosis-susceptible PIDs, including severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial diseases. PMID:22430715

  16. Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency

    PubMed Central

    Al-Herz, Waleed; Bousfiha, Aziz; Casanova, Jean-Laurent; Chatila, Talal; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Franco, Jose Luis; Gaspar, H. Bobby; Holland, Steven M.; Klein, Christoph; Nonoyama, Shigeaki; Ochs, Hans D.; Oksenhendler, Erik; Picard, Capucine; Puck, Jennifer M.; Sullivan, Kate; Tang, Mimi L. K.

    2014-01-01

    We report the updated classification of primary immunodeficiencies (PIDs) compiled by the Expert Committee of the International Union of Immunological Societies. In comparison to the previous version, more than 30 new gene defects are reported in this updated version. In addition, we have added a table of acquired defects that are phenocopies of PIDs. For each disorder, the key clinical and laboratory features are provided. This classification is the most up-to-date catalog of all known PIDs and acts as a current reference of the knowledge of these conditions and is an important aid for the molecular diagnosis of patients with these rare diseases. PMID:24795713

  17. Primary immunodeficiencies underlying fungal infections

    PubMed Central

    Lanternier, Fanny; Cypowyj, Sophie; Picard, Capucine; Bustamante, Jacinta; Lortholary, Olivier; Casanova, Jean-Laurent; Puel, Anne

    2014-01-01

    Purpose of review We review the primary immunodeficiencies underlying an increasing variety of superficial and invasive fungal infections. We also stress that the occurrence of such fungal infections should lead physicians to search for the corresponding single-gene inborn errors of immunity. Finally, we suggest that other fungal infections may also result from hitherto unknown inborn errors of immunity, at least in some patients with no known risk factors. Recent findings An increasing number of primary immunodeficiencies are being shown to underlie fungal infectious diseases in children and young adults. Inborn errors of the phagocyte NADPH oxidase complex (chronic granulomatous disease), severe congenital neutropenia and leukocyte adhesion deficiency type I confer a predisposition to invasive aspergillosis and candidiasis. More rarely, inborn errors of IFN-γ immunity underlie endemic mycoses. Inborn errors of IL-17 immunity have recently been shown to underlie chronic mucocutaneous candidiasis, whereas inborn errors of CARD9 immunity underlie deep dermatophytosis and invasive candidiasis. Summary Chronic mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, deep dermatophytosis, pneumocystosis, and endemic mycoses can all be caused by primary immunodeficiencies. Each type of infection is highly suggestive of a specific type of primary immunodeficiency. In the absence of overt risk factors, single-gene inborn errors of immunity should be sought in children and young adults with these and other fungal diseases. PMID:24240293

  18. Next Generation Sequencing Data Analysis in Primary Immunodeficiency Disorders - Future Directions.

    PubMed

    Fang, Mingyan; Abolhassani, Hassan; Lim, Che Kang; Zhang, Jianguo; Hammarström, Lennart

    2016-05-01

    Primary immunodeficiency diseases (PIDs) comprise a group of highly heterogeneous immune system diseases and around 300 forms of PID have been described to date. Next Generation Sequencing (NGS) has recently become an increasingly used approach for gene identification and molecular diagnosis of human diseases. Herein we summarize the practical considerations for the interpretation of NGS data and the techniques for searching disease-related PID genes, and suggest future directions for research in this field. PMID:26993986

  19. Human Immunodeficiency Virus (HIV) Primary Infection

    MedlinePlus

    ... rashes clinical tools newsletter | contact Share | Human Immunodeficiency Virus (HIV) Primary Infection Information for adults A A ... weeks following exposure to HIV (the human immunodeficiency virus). Chronic infection with this virus can cause AIDS ( ...

  20. Invasive aspergillosis in primary immunodeficiencies.

    PubMed

    Almyroudis, N G; Holland, S M; Segal, B H

    2005-05-01

    Primary immunodeficiencies are rare and usually first manifest during childhood. Invasive aspergillosis is the leading cause of mortality in chronic granulomatous disease (CGD), reflecting the key role of the phagocyte NADPH oxidase in host defense against opportunistic fungi. Despite interferon-gamma prophylaxis, invasive filamentous fungal infections are a persistent problem in CGD. Key principles of management of fungal infections involve early recognition and aggressive treatment and appropriate surgical debridement of localized disease. Because CGD is a disorder of phagocyte stem cells in which the gene defects are well defined, it is a model disease to evaluate immune reconstitution through stem cell transplantation and gene therapy. Patients with the hyper-IgE syndrome with recurrent infections (Job syndrome) are prone to colonization of lung cavities (pneumatoceles) by Aspergillus species leading to local invasion and rarely disseminated infection. Other primary phagocytic disorders, T-cell disorders, and mitochondrial disorders are uncommonly associated with invasive aspergillosis. Taken together, these rare primary immunodeficiencies highlight the complex coordination of both innate and acquired pathways mediating host defense against Aspergillus infection. PMID:16110817

  1. The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008.

    PubMed

    Gathmann, B; Grimbacher, B; Beauté, J; Dudoit, Y; Mahlaoui, N; Fischer, A; Knerr, V; Kindle, G

    2009-09-01

    Primary immunodeficiencies (PID) are rare diseases; therefore transnational studies are essential to maximize the scientific outcome and to improve diagnosis and therapy. In order to estimate the prevalence of PID in Europe as well as to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Within 4 years, 7430 patients from 39 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity, with 1540 patients or 20.7% of all entries, followed by isolated immunoglobulin (Ig)G subclass deficiency (546 patients, 7.4%). Evaluations show that the average life expectancy for PID patients varies from 1 to 49 years (median), depending on the type of PID. The prevalence and incidence of PID remains a key question to be answered. As the registration progress is far from finished we can only calculate minimum values for PID, with e.g. France currently showing a minimum prevalence of 3.72 patients per 100,000 inhabitants. The most frequently documented permanent treatment is immunoglobulin replacement; 2819 patients (42% of all patients alive) currently receive this form of treatment. PMID:19630863

  2. Novel Primary Immunodeficiency Candidate Genes Predicted by the Human Gene Connectome

    PubMed Central

    Itan, Yuval; Casanova, Jean-Laurent

    2015-01-01

    Germline genetic mutations underlie various primary immunodeficiency (PID) diseases. Patients with rare PID diseases (like most non-PID patients and healthy individuals) carry, on average, 20,000 rare and common coding variants detected by high-throughput sequencing. It is thus a major challenge to select only a few candidate disease-causing variants for experimental testing. One of the tools commonly used in the pipeline for estimating a potential PID-candidate gene is to test whether the specific gene is included in the list of genes that were already experimentally validated as PID-causing in previous studies. However, this approach is limited because it cannot detect the PID-causing mutation(s) in the many PID patients carrying causal mutations of as yet unidentified PID-causing genes. In this study, we expanded in silico the list of potential PID-causing candidate genes from 229 to 3,110. We first identified the top 1% of human genes predicted by the human genes connectome to be biologically close to the 229 known PID genes. We then further narrowed down the list of genes by retaining only the most biologically relevant genes, with functionally enriched gene ontology biological categories similar to those for the known PID genes. We validated this prediction by showing that 17 of the 21 novel PID genes published since the last IUIS classification fall into this group of 3,110 genes (p < 10−7). The resulting new extended list of 3,110 predicted PID genes should be useful for the discovery of novel PID genes in patients. PMID:25883595

  3. Pharmacoeconomics of immunoglobulins in primary immunodeficiency.

    PubMed

    Simoens, Steven

    2009-08-01

    Primary immunodeficiency disorders are associated with increased patient susceptibility to recurrent infections. Since the 1950s, intramuscular, intravenous and subcutaneous immunoglobulin products have been used to replace functionally deficient or absent immunoglobulins, reduce the incidence of infections and prevent organ damage caused by infections. This article aims to review the use of immunoglobulin therapy in primary immunodeficiency by focusing on costs, effectiveness, cost-effectiveness, supply and off-label use. To date, the economic burden of primary immunodeficiency is unknown. Past studies have supported minimal differences in effectiveness between intravenous and subcutaneous immunoglobulins. Subcutaneous therapy may be considered for patients who prefer treatment at home. The small number of economic evaluations and their methodological limitations precludes the recommendation of a specific product for use in primary immunodeficiency on pharmacoeconomic grounds. Demand for immunoglobulins has increased over time, leading to periodic shortages and emphasizing the importance of its appropriate use. PMID:19670998

  4. Warts and All: HPV in Primary Immunodeficiencies

    PubMed Central

    Leiding, Jennifer W.; Holland, Steven M.

    2012-01-01

    Infection with human papilloma virus (HPV) is almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy. It is also an underappreciated manifestation of primary immunodeficiency. Mutations in EVER1, EVER2, GATA2, CXCR4, and DOCK8 are typically associated with extensive HPV infections, whereas several other primary immune defects have severe HPV much less frequently. We review immunodeficiencies with severe HPV infections and the mechanisms underlying them. PMID:23036745

  5. Severe Viral Infections and Primary Immunodeficiencies

    PubMed Central

    Cohen, Jeffrey I.

    2011-01-01

    Patients with severe viral infections are often not thoroughly evaluated for immunodeficiencies. In this review, we summarize primary immunodeficiencies that predispose individuals to severe viral infections. Some immunodeficiencies enhance susceptibility to disease with a specific virus or family of viruses, whereas others predispose to diseases with multiple viruses in addition to disease with other microbes. Although the role of cytotoxic T cells in controlling viral infections is well known, a number of immunodeficiencies that predispose to severe viral diseases have recently been ascribed to defects in the Toll-like receptor–interferon signaling pathway. These immunodeficiencies are rare, but it is important to identify them both for prognostic information and for genetic counseling. Undoubtedly, additional mutations in proteins in the innate and adaptive arms of the immune system will be identified in the future, which will reveal the importance of these proteins in controlling infections caused by viruses and other pathogens. PMID:21960712

  6. Invasive Pneumococcal Disease in Children Can Reveal a Primary Immunodeficiency

    PubMed Central

    Gaschignard, Jean; Levy, Corinne; Chrabieh, Maya; Boisson, Bertrand; Bost-Bru, Cécile; Dauger, Stéphane; Dubos, François; Durand, Philippe; Gaudelus, Joël; Gendrel, Dominique; Gras Le Guen, Christèle; Grimprel, Emmanuel; Guyon, Gaël; Jeudy, Catherine; Jeziorski, Eric; Leclerc, Francis; Léger, Pierre-Louis; Lesage, Fabrice; Lorrot, Mathie; Pellier, Isabelle; Pinquier, Didier; de Pontual, Loïc; Sachs, Philippe; Thomas, Caroline; Tissières, Pierre; Valla, Frédéric V.; Desprez, Philippe; Frémeaux-Bacchi, Véronique; Varon, Emmanuelle; Bossuyt, Xavier; Cohen, Robert; Abel, Laurent; Casanova, Jean-Laurent; Puel, Anne; Picard, Capucine

    2014-01-01

    Background. About 10% of pediatric patients with invasive pneumococcal disease (IPD) die from the disease. Some primary immunodeficiencies (PIDs) are known to confer predisposition to IPD. However, a systematic search for these PIDs has never been carried out in children presenting with IPD. Methods. We prospectively identified pediatric cases of IPD requiring hospitalization between 2005 and 2011 in 28 pediatric wards throughout France. IPD was defined as a positive pneumococcal culture, polymerase chain reaction result, and/or soluble antigen detection at a normally sterile site. The immunological assessment included abdominal ultrasound, whole-blood counts and smears, determinations of plasma immunoglobulin and complement levels, and the evaluation of proinflammatory cytokines. Results. We included 163 children with IPD (male-to-female ratio, 1.3; median age, 13 months). Seventeen children had recurrent IPD. Meningitis was the most frequent type of infection (87%); other infections included pleuropneumonitis, isolated bloodstream infection, osteomyelitis, endocarditis, and mastoiditis. One patient with recurrent meningitis had a congenital cerebrospinal fluid fistula. The results of immunological explorations were abnormal in 26 children (16%), and a PID was identified in 17 patients (10%), including 1 case of MyD88 deficiency, 3 of complement fraction C2 or C3 deficiencies, 1 of isolated congenital asplenia, and 2 of Bruton disease (X-linked agammaglobulinemia). The proportion of PIDs was much higher in children aged >2 years than in younger children (26% vs 3%; P < .001). Conclusions. Children with IPD should undergo immunological investigations, particularly those aged >2 years, as PIDs may be discovered in up to 26% of cases. PMID:24759830

  7. Clinical applications of gene therapy for primary immunodeficiencies.

    PubMed

    Cicalese, Maria Pia; Aiuti, Alessandro

    2015-04-01

    Primary immunodeficiencies (PIDs) have represented a paradigmatic model for successes and pitfalls of hematopoietic stem cells gene therapy. First clinical trials performed with gamma retroviral vectors (γ-RV) for adenosine deaminase severe combined immunodeficiency (ADA-SCID), X-linked SCID (SCID-X1), and Wiskott-Aldrich syndrome (WAS) showed that gene therapy is a valid therapeutic option in patients lacking an HLA-identical donor. No insertional mutagenesis events have been observed in more than 40 ADA-SCID patients treated so far in the context of different clinical trials worldwide, suggesting a favorable risk-benefit ratio for this disease. On the other hand, the occurrence of insertional oncogenesis in SCID-X1, WAS, and chronic granulomatous disease (CGD) RV clinical trials prompted the development of safer vector construct based on self-inactivating (SIN) retroviral or lentiviral vectors (LVs). Here we present the recent results of LV-mediated gene therapy for WAS showing stable multilineage engraftment leading to hematological and immunological improvement, and discuss the differences with respect to the WAS RV trial. We also describe recent clinical results of SCID-X1 gene therapy with SIN γ-RV and the perspectives of targeted genome editing techniques, following early preclinical studies showing promising results in terms of specificity of gene correction. Finally, we provide an overview of the gene therapy approaches for other PIDs and discuss its prospects in relation to the evolving arena of allogeneic transplant. PMID:25860576

  8. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

    PubMed Central

    2014-01-01

    Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches. PMID:25163701

  9. The European internet-based patient and research database for primary immunodeficiencies: results 2004-06.

    PubMed

    Eades-Perner, A-M; Gathmann, B; Knerr, V; Guzman, D; Veit, D; Kindle, G; Grimbacher, B

    2007-02-01

    Because primary immunodeficiencies (PID) are rare diseases, transnational studies are essential to maximize the scientific outcome and lead to improved diagnosis and therapy. Immunologists in Europe have united to determine the prevalence of PID in Europe and to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID as well as to improve the awareness of PID in Europe. In order to achieve this aim we have developed an internet-based database for clinical and research data on patients with PID. This database forms the platform for studies of demographics, the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. The database is completely secure, while providing access to researchers via a standard browser using password and encrypted log-in sessions and conforms to all European and national ethics and data protection guidelines. So far 2386 patients have been documented by 35 documenting centres in 20 countries. Common variable immunodeficiency (CVID) is the most common entity, accounting for almost 30% of all entries. First statistical analyses on the quality of life of patients show the advantages of immunoglobulin replacement therapy, at the same time revealing a mean diagnostic delay of over 4 years. First studies on specific questions on selected PID are now under way. The platform of this database can be used for any type of medical condition. PMID:17223972

  10. Advances of gene therapy for primary immunodeficiencies

    PubMed Central

    Candotti, Fabio

    2016-01-01

    In the recent past, the gene therapy field has witnessed a remarkable series of successes, many of which have involved primary immunodeficiency diseases, such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic granulomatous disease, and Wiskott-Aldrich syndrome. While such progress has widened the choice of therapeutic options in some specific cases of primary immunodeficiency, much remains to be done to extend the geographical availability of such an advanced approach and to increase the number of diseases that can be targeted. At the same time, emerging technologies are stimulating intensive investigations that may lead to the application of precise genetic editing as the next form of gene therapy for these and other human genetic diseases. PMID:27508076

  11. F-actin remodeling defects as revealed in primary immunodeficiency disorders.

    PubMed

    Janssen, W J M; Geluk, H C A; Boes, M

    2016-03-01

    Primary immunodeficiencies (PIDs) are a heterogeneous group of immune-related diseases. PIDs develop due to defects in gene-products that have consequences to immune cell function. A number of PID-proteins is involved in the remodeling of filamentous actin (f-actin) to support the generation of a contact zone between the antigen-specific T cell and antigen presenting cell (APC): the immunological synapse (IS). IS formation is the first step towards T-cell activation and essential for clonal expansion and acquisition of effector function. We here evaluated PIDs in which aberrant f-actin-driven IS formation may contribute to the PID disease phenotypes as seen in patients. We review examples of such contributions to PID phenotypes from literature, and highlight cases in which PID-proteins were evaluated for a role in f-actin polymerization and IS formation. We conclude with the proposition that patient groups might benefit from stratifying them in distinct functional groups in regard to their f-actin remodeling phenotypes in lymphocytes. PMID:26802313

  12. Single-institution Experience of Unrelated Cord Blood Transplantation for Primary Immunodeficiency.

    PubMed

    Chang, Tsung-Yun; Jaing, Tang-Her; Lee, Wei-I; Chen, Shih-Hsiang; Yang, Chao-Ping; Hung, Iou-Jih

    2015-04-01

    Pediatric patients with primary immunodeficiencies (PID) constitute life-threatening medical emergencies. In the absence of an HLA-identical hematopoietic stem cell donor, unrelated donor cord blood transplantation (CBT) is another treatment option. There are little data regarding the outcome of unrelated CBT for PID in Taiwan. We report the results of CBT performed in 8 patients with PID between 2004 and 2013 at Chang Gung Memorial Hospital. The cases included severe combined immunodeficiency (n=4), chronic granulomatous disease (n=2), Wiskott-Aldrich syndrome (n=1), and T-cell immunodeficiency (n=1). Median follow-up time was 73 months. Most UCB recipients received a myeloablative conditioning regimen. There were 7 boys and 1 girl with a median age of 2.5 months at diagnosis (range, antenatal to 17 mo). Median age at transplant was 5.5 months (range, 2 to 74 mo). All but 1 patients engrafted at a median time of 14 days. One developed significant grade III graft-versus-host disease after transplant. Our data show that unrelated CBT in PID is possible. However, no definite conclusions can be drawn from this small number of patients, and more studies are needed to further investigate and confirm these findings. PMID:25089606

  13. Lentiviral vectors for the treatment of primary immunodeficiencies.

    PubMed

    Farinelli, Giada; Capo, Valentina; Scaramuzza, Samantha; Aiuti, Alessandro

    2014-07-01

    In the last years important progress has been made in the treatment of several primary immunodeficiency disorders (PIDs) with gene therapy. Hematopoietic stem cell (HSC) gene therapy indeed represents a valid alternative to conventional transplantation when a compatible donor is not available and recent success confirmed the great potential of this approach. First clinical trials performed with gamma retroviral vectors were promising and guaranteed clinical benefits to the patients. On the other hand, the outcome of severe adverse events as the development of hematological abnormalities highlighted the necessity to develop a safer platform to deliver the therapeutic gene. Self-inactivating (SIN) lentiviral vectors (LVVs) were studied to overcome this hurdle through their preferable integration pattern into the host genome. In this review, we describe the recent advancements achieved both in vitro and at preclinical level with LVVs for the treatment of Wiskott-Aldrich syndrome (WAS), chronic granulomatous disease (CGD), ADA deficiency (ADA-SCID), Artemis deficiency, RAG1/2 deficiency, X-linked severe combined immunodeficiency (γchain deficiency, SCIDX1), X-linked lymphoproliferative disease (XLP) and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. PMID:24619149

  14. Pulmonary Manifestations of Primary Immunodeficiency Disorders.

    PubMed

    Nonas, Stephanie

    2015-11-01

    Pulmonary disease, ranging from infectious pneumonia, lung abscess, and empyema to structural lung diseases to malignancy, significantly increase morbidity and mortality in primary immune deficiency. Treatment with supplemental immunoglobulin (intravenous or subcutaneous) and antimicrobials is beneficial in reducing infections but are largely ineffective in preventing noninfectious complications, including interstitial lung disease, malignancy, and autoimmune disease. A low threshold for suspecting pulmonary complications is necessary for the early diagnosis of pulmonary involvement in primary immunodeficiency disorders, before irreversible damage is done, to improve patient outcomes. PMID:26454317

  15. [Primary immunodeficiencies presenting with autoimmune cytopenias in adults].

    PubMed

    Sève, P; Broussolle, C; Pavic, M

    2013-03-01

    Although primary immunodeficiencies (PID) are typically marked by increased susceptibility to infections, autoimmune manifestations have increasingly been recognized as an important component of several forms of PID. Here, we discuss two forms of PID in which autoimmune cytopenias are particularly common and may be the first manifestation of the disease in adults: autoimmune lymphoproliferative syndrome (ALPS) and common variable immunodeficiency (CVID). Approximately one fifth of patients with CVID develop autoimmune diseases, and immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AHA) are the most common. Since autoimmune cytopenias frequently precede the diagnosis of CVID, testing for immunoglobulin levels should be performed in patients diagnosed with AITP and AHA. Patients with CVID in association with autoimmune cytopenias have a "particular phenotype" with lower susceptibility to infection and higher susceptibility to autoimmune manifestations and, for patients with AHA, a more frequent development of splenomegaly and lymphoma. Corticosteroids and high doses of intravenous immunoglobulins (IVIg) seem to have the same efficacy as in idiopathic AITP and AHA. Splenectomy and rituximab are as effective as in idiopathic autoimmune cytopenias but are associated with an increased risk of severe infection and should, in our opinion, be considered only for those rare patients with "refractory diseases". The course and outcome of autoimmune cytopenias is not affected by supportive IVIg therapy. Autoimmune destruction of blood cells affects over 70% of ALPS patients. The median age of first presentation is 24 months of age, but with increasing awareness of this condition, adults with autoimmune cytopenias are now being diagnosed more frequently. Testing for ALPS should therefore be considered in young adults with unexplained Evan's syndrome. Patients usually respond to immunosuppressive medications, including corticosteroids. Unlike many patients

  16. Comparison of American and European practices in the management of patients with primary immunodeficiencies

    PubMed Central

    Hernandez-Trujillo, H S; Chapel, H; Lo Re III, V; Notarangelo, L D; Gathmann, B; Grimbacher, B; Boyle, J M; Hernandez-Trujillo, V P; Scalchunes, C; Boyle, M L; Orange, J S

    2012-01-01

    Primary immunodeficiency diseases (PIDs) comprise a heterogeneous group of rare disorders. This study was devised in order to compare management of these diseases in the northern hemisphere, given the variability of practice among clinicians in North America. The members of two international societies for clinical immunologists were asked about their management protocols in relation to their PID practice. An anonymous internet questionnaire, used previously for a survey of the American Academy of Allergy, Asthma and Immunology (AAAAI), was offered to all full members of the European Society for Immunodeficiency (ESID). The replies were analysed in three groups, according to the proportion of PID patients in the practice of each respondent; this resulted in two groups from North America and one from Europe. The 123 responses from ESID members (23·7%) were, in the majority, very similar to those of AAAAI respondents, with > 10% of their practice devoted to primary immunodeficiency. There were major differences between the responses of these two groups and those of the general AAAAI respondents whose clinical practice was composed of < 10% of PID patients. These differences included the routine use of intravenous immunoglobulin therapy (IVIg) for particular types of PIDs, initial levels of IVIg doses, dosing intervals, routine use of prophylactic antibiotics, perceptions of the usefulness of subcutaneous immunoglobulin therapy (SCIg) and of the risk to patients' health of policies adopted by health-care funders. Differences in practice were identified and are discussed in terms of methods of health-care provision, which suggest future studies for ensuring continuation of appropriate levels of immunoglobulin replacement therapies. PMID:22670779

  17. [Primary immunodeficiency in adults: common variable immunodeficiency--clinical manifestations, immunological and genetic defects, treatment].

    PubMed

    2011-01-01

    The most prevalent form of primary immunodeficiency with a total defect of antibody production in adults is common variable immunodeficiency (CVID). Compared to other forms of primary immunodeficiency, CVID is characterized by later onset of clinical manifestations represented by infectious, autoimmune and malignant diseases. To avoid development of complications and patient incapacitation, it is necessary to make an early diagnosis and initiate regular replacement therapy with intravenous immunoglobulins. PMID:22185026

  18. Early-Onset Autoimmune Disease as a Manifestation of Primary Immunodeficiency

    PubMed Central

    Carneiro-Sampaio, Magda; Coutinho, Antonio

    2015-01-01

    Autoimmune disorders (AID) have been increasingly observed in association with primary immunodeficiencies (PIDs). Here, we discuss the interface between PID and AID, focusing on autoimmune manifestations early in life, which can be diagnostic clues for underlying PIDs. Inflammatory bowel disease in infants and children has been associated with IL-10 and IL-10R deficiencies, chronic granulomatous disease, immunedysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (IPEX), autoinflammatory disorders, and others. Some PIDs have been identified as underlying defects in juvenile systemic lupus erythematosus: C1q-, IgA-, IgM deficiencies, alterations of the IFN-α pathway (in Aicardi–Goutières syndrome due to TREX1 mutation). IPEX (due to FOXP3 mutation leading to Treg cell deficiency), usually appearing in the first months of life, was recently observed in miscarried fetuses with hydrops who presented with CD3+ infiltrating lymphocytes in the pancreas. Hemophagocytic lymphohistiocytosis due to perforin deficiency was also identified as a cause of fetal hydrops. In conclusion, PID should be suspected in any infant with signs of autoimmunity after excluding transferred maternal effects, or in children with multiple and/or severe AID. PMID:25999944

  19. The altered landscape of the human skin microbiome in patients with primary immunodeficiencies

    PubMed Central

    Oh, Julia; Freeman, Alexandra F.; Park, Morgan; Sokolic, Robert; Candotti, Fabio; Holland, Steven M.; Segre, Julia A.; Kong, Heidi H.

    2013-01-01

    While landmark studies have shown that microbiota activate and educate host immunity, how immune systems shape microbiomes and contribute to disease is incompletely characterized. Primary immunodeficiency (PID) patients suffer recurrent microbial infections, providing a unique opportunity to address this issue. To investigate the potential influence of host immunity on the skin microbiome, we examined skin microbiomes in patients with rare monogenic PIDs: hyper-IgE (STAT3-deficient), Wiskott-Aldrich, and dedicator of cytokinesis 8 syndromes. While specific immunologic defects differ, a shared hallmark is atopic dermatitis (AD)–like eczema. We compared bacterial and fungal skin microbiomes (41 PID, 13 AD, 49 healthy controls) at four clinically relevant sites representing the major skin microenvironments. PID skin displayed increased ecological permissiveness with altered population structures, decreased site specificity and temporal stability, and colonization with microbial species not observed in controls, including Clostridium species and Serratia marcescens. Elevated fungal diversity and increased representation of opportunistic fungi (Candida, Aspergillus) supported increased PID skin permissiveness, suggesting that skin may serve as a reservoir for the recurrent fungal infections observed in these patients. The overarching theme of increased ecological permissiveness in PID skin was counterbalanced by the maintenance of a phylum barrier in which colonization remained restricted to typical human-associated phyla. Clinical parameters, including markers of disease severity, were positively correlated with prevalence of Staphylococcus, Corynebacterium, and other less abundant taxa. This study examines differences in microbial colonization and community stability in PID skin and informs our understanding of host–microbiome interactions, suggesting a bidirectional dialogue between skin commensals and the host organism. PMID:24170601

  20. The European internet-based patient and research database for primary immunodeficiencies: update 2011.

    PubMed

    Gathmann, B; Binder, N; Ehl, S; Kindle, G

    2012-03-01

    In order to build a common data pool and estimate the disease burden of primary immunodeficiencies (PID) in Europe, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Since its start in 2004, 13,708 patients from 41 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity with 2880 patients or 21% of all entries, followed by selective immunoglobulin A (sIgA) deficiency (1424 patients, 10·4%). The total documented prevalence of PID is highest in France, with five patients per 100,000 inhabitants. The highest documented prevalence for a single disease is 1·3 per 100,000 inhabitants for sIgA deficiency in Hungary. The highest reported incidence of PID per 100,000 live births was 16·2 for the period 1999-2002 in France. The highest reported incidence rate for a single disease was 6·7 for sIgA deficiency in Spain for the period 1999-2002. The genetic cause was known in 36·2% of all registered patients. Consanguinity was reported in 8·8%, and 18·5% of patients were reported to be familial cases; 27·9% of patients were diagnosed after the age of 16. We did not observe a significant decrease in the diagnostic delay for most diseases between 1987 and 2010. The most frequently reported long-term medication is immunoglobulin replacement. PMID:22288591

  1. Primary immunodeficiencies of the B lymphocyte.

    PubMed

    Moise, Ana; Nedelcu, Filofteia Daniela; Toader, Maria Adela; Sora, Steluta Mihaela; Tica, Anca; Ferastraoaru, Denisa Elena; Constantinescu, Ileana

    2010-01-01

    The immune response consists of two main components: humoral immunity represented by B lymphocytes and cellular immunity maintained by the T lymphocytes. Immunoglobulins, produced by B-lymphocytes, are the main mediators of humoral immunity, and deficiencies at this level affect the body's response to infection. Plasmocytes produce nine antibody izotypes: immunoglobulins G (IgG1, IgG2, IgG3, IgG4), immunoglobulins M (IgM), immunoglobulins A (IgA1, IgA2), immunoglobulins D (IGD) and immunoglobulins E (IgE). Primary hypogammaglobulinemias are characterized by the occurrence of recurrent infections and, paradoxically, by the occurrence of autoimmune diseases. Characteristic for these diseases is that symptoms occur at 7-9 months after birth, when transplacental antibody titers transmitted from the mother decrease, and the infant's body is unable to synthesize them to normal levels. Primary hypogammaglobulinemias are transmitted genetically, but mutations at the molecular level are still not fully understood. The most common are: Bruton agammaglobulinemia, transient newborn hypogammaglobulinemia, selective immunoglobulin deficiency and variable common immunodeficiency. Treatment consists of monthly antibiotics and immunoglobulins, depending on antibody titers (except for IgA deficiency). PMID:20302197

  2. Primary Immunodeficiency May Be Misdiagnosed as Cow's Milk Allergy: Seven Cases Referred to a Tertiary Pediatric Hospital

    PubMed Central

    Melo, Karina Mescouto; Dantas, Ellen; De Moraes-Pinto, Maria Isabel; Condino-Neto, Antonio; Gonzalez, Isabela G. S.; Mallozi, Marcia C.; Franco, Jackeline M.; Costa-Carvalho, Beatriz T.

    2013-01-01

    Introduction. The presence of eczema and gastrointestinal manifestations are often observed in cow's milk allergy (CMA) and also in some primary immunodeficiency diseases (PID). Objective. To describe 7 patients referred to a tertiary allergy/immunology Center with a proposed diagnosis of CMA, who were ultimately diagnosed with PID. Methods. This was a retrospective study based on clinical and laboratory data from medical records. Results. Seven patients (6 males) aged between 3 mo and 6 y were referred to our clinic with a proposed diagnosis of CMA. They presented with eczema and/or gastrointestinal symptoms. Five were receiving replacement formula. All patients presented with other clinical features, including severe/recurrent infections unrelated to CMA, and two of them had a positive family history of PID. Laboratory tests showed immune system dysfunctions in all patients. Hyper-IgE and Wiskott-Aldrich syndromes, CD40L deficiency, severe combined immunodeficiency, X-linked agammaglobulinemia, transient hypogammaglobulinemia of infancy, and chronic granulomatous disease were diagnosed in these children. In conclusion, allergic diseases and immunodeficiency are a result of a different spectrum of abnormalities in the immune system and may be misdiagnosed. Educational programs on PID among clinical physicians and pediatricians can reduce the occurrence of this misdiagnosis. PMID:24198970

  3. THE IMPORTANCE OF EDUCATING PEDIATRICIANS ABOUT PRIMARY IMMUNODEFICIENCY DISORDERS: A TERTIARY HOSPITAL EXPERIENCE.

    PubMed

    Adeli, M; Hendaus, M; Imam, L; Alhammadi, A

    2015-09-01

    Primary immunodeficiency disorders (PIDs) are several genetic disorders that alter the essential components of the immune system leading to errors in differentiation, function or both of these components.There are more than 200 reported different PID diseases with more than 140 identified gene mutations, affecting almost six million individuals globally, but only 27,000-60,000 have being diagnosed.Early diagnosis of PIDs can markedly reduce morbidity and mortality via proper intervention The aim of the study was to estimate the knowledge and attitude of pediatric residents of PIDs.To the best of our knowledge, this is the first study that targets resident physicians in the field of PIDs. A prospective and cross-sectional study was conducted at Hamad Medical Corporation, the only tertiary care, academic and teaching hospital in the state of Qatar. The study took place between January, 2014 and April 30, 2014. A self-administered questionnaire was distributed to 68 pediatric residents (post-graduate year 1-4). In all, 68 eligible resident physicians were included in the study. Out of the 68 questionnaires distributed, 59 (86.7%) were returned by the end of the study. Among the participants, 18 (30.5%) were post-graduate year-1 (PGY-1), 18 (30.5%) PGY-2, 11 (18.6%) PGY-3, and 12 (20.3%) PGY-4.The mean overall score was 58.5 %. The mean score in the clinical presentation was 67.5%, in associated syndromes and diseases was 59%, in screening laboratory work up 55.3%, and in the section of laboratory investigations that suggest PIDs 52%. There is a significant lack of knowledge of PIDs among pediatric residents. In addition, a large number of pediatric physicians in training do not feel comfortable in diagnosing and managing young children with PIDs. Pediatric residency working hours rule restrict the luxury of having an allergy/immunology rotation during residency. A mutual effort in sharing diagnosis and management of patients with PIDs between pediatric residents and

  4. Stem cell transplantation for primary immunodeficiency diseases: The North American Experience

    PubMed Central

    Pai, Sung-Yun; Cowan, Morton J.

    2014-01-01

    Purpose of the Review This review describes recent studies on outcomes after allogeneic hematopoietic cell transplantation (HCT) for primary immunodeficiency (PID) in North America including severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Recent Findings Using uniform diagnostic criteria, the Primary Immune Deficiency Treatment Consortium (PIDTC) described the baseline characteristics of newly diagnosed infants with SCID in North America. Analysis of outcomes of HCT for SCID in North America from 2000–2009 showed that young infants, and older infants without active infection, had excellent survival irrespective of type of donor, or transplant approach with regards to conditioning. While pre-transplant conditioning with chemotherapy had a clear and strong negative impact on survival in infants with active infection at the time of transplant, among survivors, conditioning was associated with improved immune reconstitution. However, the potential late effects of conditioning in these infants remain to be characterized. Advances in transplant outcomes for WAS and CGD support the strategy of early transplantation before the onset of severe complications; additional multicenter studies are needed to fully define optimal approaches. Summary The formation of the PIDTC, a multi-institutional North American consortium, has contributed to our understanding of outcomes after transplant for PID. PMID:25259542

  5. Strategies for B-Cell Receptor Repertoire Analysis in Primary Immunodeficiencies: From Severe Combined Immunodeficiency to Common Variable Immunodeficiency

    PubMed Central

    IJspeert, Hanna; Wentink, Marjolein; van Zessen, David; Driessen, Gertjan J.; Dalm, Virgil A. S. H.; van Hagen, Martin P.; Pico-Knijnenburg, Ingrid; Simons, Erik J.; van Dongen, Jacques J. M.; Stubbs, Andrew P.; van der Burg, Mirjam

    2015-01-01

    The antigen receptor repertoires of B- and T-cells form the basis of the adaptive immune response. The repertoires should be sufficiently diverse to recognize all possible pathogens. However, careful selection is needed to prevent responses to self or harmless antigens. Limited antigen receptor repertoire diversity leads to immunodeficiency, whereas unselected or misdirected repertoires can result in autoimmunity. The antigen receptor repertoire harbors information about abnormalities in many immunological disorders. Recent developments in next generation sequencing allow the analysis of the antigen receptor repertoire in much greater detail than ever before. Analyzing the antigen receptor repertoire in patients with mutations in genes responsible for the generation of the antigen receptor repertoire will give new insights into repertoire formation and selection. In this perspective, we describe strategies and considerations for analysis of the naive and antigen-selected B-cell repertoires in primary immunodeficiency patients with a focus on severe combined immunodeficiency and common variable immunodeficiency. PMID:25904919

  6. Mutation analysis in primary immunodeficiency diseases: case studies

    PubMed Central

    Hsu, Amy P.; Fleisher, Thomas A.; Niemela, Julie E.

    2009-01-01

    Purpose of review The application of mutation analysis is becoming an integral part of the complete evaluation of patients with primary immunodeficiencies, and as such, clinicians caring for these patients must develop a better understanding of the utility and challenges of this important laboratory technology. Recent findings Genomic DNA sequencing is currently the standard approach used to characterize a possible gene mutation causing a specific primary immunodeficiency. There are clinical situations in which this approach is revealing of a genetic defect and other circumstances in which this generates a false-positive or false-negative result. One case study is presented that reviews a straightforward analysis that clarifies the genetic basis of a primary immunodeficiency, and four cases are presented that required additional studies to clarify the underlying basis of the immunodeficiency. In the latter circumstances, the rationale for additional studies is outlined and the outcome of these is presented. Summary The identification of a gene mutation as the underlying basis of a primary immunodeficiency begins with the evaluation of the clinical presentation focusing on the infection history so as to develop a differential diagnosis including potential genetic causes. The next step is to obtain specific laboratory studies, including immunologic function evaluation, and, based on these findings, to proceed with DNA sequencing of one or several selected candidate genes. Genomic DNA sequencing has certain limitations, and alternative follow-up approaches may be necessary to establish the molecular basis of the primary immunodeficiency in a given patient. PMID:19841577

  7. Low-dose serotherapy improves early immune reconstitution after cord blood transplantation for primary immunodeficiencies.

    PubMed

    Lane, Jonathan P; Evans, Philippa T G; Nademi, Zohreh; Barge, Dawn; Jackson, Anthony; Hambleton, Sophie; Flood, Terry J; Cant, Andrew J; Abinun, Mario; Slatter, Mary A; Gennery, Andrew R

    2014-02-01

    Cord blood transplantation (CBT) is curative for many primary immunodeficiencies (PIDs) but is associated with risks of viral infection and graft-versus-host disease (GvHD). Serotherapy reduces GvHD but potentially increases the risk of viral infection by delaying immune reconstitution. Because many PID patients have pre-existing viral infections, the optimal dose of serotherapy is unclear. We performed a retrospective analysis in 34 consecutive PID patients undergoing CBT and compared immune reconstitution, viral infection, GvHD, mortality, and long-term immune function between high-dose (n = 11) and low-dose (n = 9) serotherapy. Serotherapy dose had no effect on neutrophil engraftment. Median CD3(+) engraftment occurred at 92.5 and 97 days for high- and low-dose serotherapy, respectively. The low-dose serotherapy group had higher CD3(+), CD4(+), and early thymic emigrant counts at 4 months compared with the high-dose group. GvHD severity and number of viral infections did not differ between serotherapy doses. Survival from the transplantation process was 90.9% for high-dose and 100% for low-dose groups. In conclusion, low-dose serotherapy enhanced T cell reconstitution and thymopoiesis during the first year after CBT with no increase in GvHD. PMID:24225641

  8. Identification of two novel mutations in patients with X-linked primary immunodeficiencies.

    PubMed

    Yu, Li; Wang, Xike; Wang, Yuchuan; Wang, Jian

    2015-04-01

    Primary immunodeficiency diseases (PID) are a heterogeneous group of inherited disorders with defects in one or more component of the immune system. In this study, we analyzed gene mutations in four X-linked PID pedigrees, which include one X- linked agammaglobulinemia (XLA) pedigree, one X-linked chronic granulomatous disease (XCGD) pedigree, and two X-linked Hyper IgM syndrome (XHIGM) pedigrees. Sequence analysis of the BTK gene revealed a novel mutation (c.1802_1803delinsGCC, p.Phe601CysfsX3) which results in the developmental arrest of B cells in the bone marrow. Sequence analysis of the CYBB gene revealed a recurrent frameshift mutation (c.1313_1314delinsT) in exon 10, which generates a premature stop codon (p.Lys438IlefsX63). One novel frameshift mutation (c.114delG, p.Ser39GlnfsX14) and one recurrent missense mutation (c.499G>C, p.Gly167Arg) were found in the CD40LG gene and cause defective T cell functioning. In conclusion, our study identified two novel mutations on the BTK and CD40LG genes in Chinese patients and established accurate and simple genetic diagnostic methods for three X-linked PID. PMID:25353698

  9. Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies

    PubMed Central

    Ott de Bruin, Lisa M.; Volpi, Stefano; Musunuru, Kiran

    2015-01-01

    Severe combined immunodeficiency (SCID) and other severe non-SCID primary immunodeficiencies (non-SCID PID) can be treated by allogeneic hematopoietic stem cell (HSC) transplantation, but when histocompatibility leukocyte antigen-matched donors are lacking, this can be a high-risk procedure. Correcting the patient’s own HSCs with gene therapy offers an attractive alternative. Gene therapies currently being used in clinical settings insert a functional copy of the entire gene by means of a viral vector. With this treatment, severe complications may result due to integration within oncogenes. A promising alternative is the use of endonucleases such as ZFNs, TALENs, and CRISPR/Cas9 to introduce a double-stranded break in the DNA and thus induce homology-directed repair. With these genome-editing tools a correct copy can be inserted in a precisely targeted “safe harbor.” They can also be used to correct pathogenic mutations in situ and to develop cellular or animal models needed to study the pathogenic effects of specific genetic defects found in immunodeficient patients. This review discusses the advantages and disadvantages of these endonucleases in gene correction and modeling with an emphasis on CRISPR/Cas9, which offers the most promise due to its efficacy and versatility. PMID:26052330

  10. Recent advances in treatment of severe primary immunodeficiencies

    PubMed Central

    Gennery, Andrew

    2015-01-01

    Primary immunodeficiencies are rare, inborn errors that result in impaired, disordered or uncontrolled immune responses. Whilst symptomatic and prophylactic treatment is available, hematopoietic stem cell transplantation is an option for many diseases, leading to cure of the immunodeficiency and establishing normal physical and psychological health. Newborn screening for some diseases, whilst improving outcomes, is focusing research on safer and less toxic treatment strategies, which result in durable and sustainable immune function without adverse effects. New conditioning regimens have reduced the risk of hematopoietic stem cell transplantation, and new methods of manipulating stem cell sources should guarantee a donor for almost all patients. Whilst incremental enhancements in transplantation technique have gradually improved survival outcomes over time, some of these new applications are likely to radically alter our approach to treating primary immunodeficiencies. PMID:26918153

  11. Primary immunodeficiency association with systemic lupus erythematosus: review of literature and lessons learned by the Rheumatology Division of a tertiary university hospital at São Paulo, Brazil.

    PubMed

    Errante, Paolo Ruggero; Perazzio, Sandro Félix; Frazão, Josias Brito; da Silva, Neusa Pereira; Andrade, Luis Eduardo Coelho

    2016-01-01

    Primary immunodeficiency disorders (PID) represent a heterogeneous group of diseases resulting from inherited defects in the development, maturation and normal function of immune cells; thus, turning individuals susceptible to recurrent infections, allergy, autoimmunity, and malignancies. In this retrospective study, autoimmune diseases (AIDs), in special systemic lupus erythematosus (SLE) which arose associated to the course of PID, are described. Classically, the literature describes three groups of PID associated with SLE: (1) deficiency of Complement pathway components, (2) defects in immunoglobulin synthesis, and (3) chronic granulomatous disease (CGD). Currently, other PID have been described with clinical manifestation of SLE, such as Wiskott-Aldrich syndrome (WAS), autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), autoimmune lymphoproliferative syndrome (ALPS) and idiopathic CD4(+) lymphocytopenia. Also we present findings from an adult cohort from the outpatient clinic of the Rheumatology Division of Universidade Federal de São Paulo. The PID manifestations found by our study group were considered mild in terms of severity of infections and mortality in early life. Thus, it is possible that some immunodeficiency states are compatible with survival regarding infectious susceptibility; however these states might represent a strong predisposing factor for the development of immune disorders like those observed in SLE. PMID:27267335

  12. Application of Flow Cytometry in the Evaluation of Primary Immunodeficiencies.

    PubMed

    Fleisher, Thomas A; Madkaikar, Manisha; Rosenzweig, Sergio D

    2016-05-01

    Primary immunodeficiency disorders (PIDDs) are a heterogeneous group of inherited disorders of the immune system. Currently more than 250 different PIDDs with a known genetic defect have been recognized. The diagnosis of many of these disorders is supported strongly by a wide variety of flow cytometry applications. Flow cytometry offers a rapid and sensitive tool for diagnosis and classification of PIDDs. It is applicable in the initial workup and subsequent management of several primary immunodeficiency diseases. As our understanding of the pathogenesis and management of these diseases increases, the majority of these tests can be easily established in the diagnostic laboratory. Thus, the focus of this article is on the application of flow cytometry in the diagnosis and/or evaluation of PIDDs. PMID:26865168

  13. Hyaluronidase facilitated subcutaneous immunoglobulin in primary immunodeficiency

    PubMed Central

    Jolles, Stephen

    2013-01-01

    Immunoglobulin (Ig)-replacement therapy represents the mainstay of treatment for patients with primary antibody deficiency and is administered either intravenously (IVIg) or subcutaneously (SCIg). While hyaluronidase has been used in clinical practice for over 50 years, the development of a high-purity recombinant form of this enzyme (recombinant human hyaluronidase PH20) has recently enabled the study of repeated and more prolonged use of hyaluronidase in facilitating the delivery of SC medicines. It has been used in a wide range of clinical settings to give antibiotics, local anesthetics, insulin, morphine, fluid replacement, and larger molecules, such as antibodies. Hyaluronidase has been used to help overcome the limitations on the maximum volume that can be delivered into the SC space by enabling dispersion of SCIg and its absorption into lymphatics. The rate of facilitated SCIg (fSCIg) infusion is equivalent to that of IVIg, and the volume administered at a single site can be greater than 700 mL, a huge increase over conventional SCIg, at 20–40 mL. The use of fSCIg avoids the higher incidence of systemic side effects of IVIg, and it has higher bioavailability than SCIg. Data on the long-term safety of this approach are currently lacking, as fSCIg has only recently become available. fSCIg may help several areas of patient management in primary antibody deficiency, and the extent to which it may be used in future will depend on long-term safety data and cost–benefit analysis.

  14. Respiratory Syncytial Virus Infections in Infants Affected by Primary Immunodeficiency

    PubMed Central

    Capretti, Maria Grazia; Lazzarotto, Tiziana; Faldella, Giacomo

    2014-01-01

    Primary immunodeficiencies are rare inherited disorders that may lead to frequent and often severe acute respiratory infections. Respiratory syncytial virus (RSV) is one of the most frequent pathogens during early infancy and the infection is more severe in immunocompromised infants than in healthy infants, as a result of impaired T- and B-cell immune response unable to efficaciously neutralize viral replication, with subsequent increased viral shedding and potentially lethal lower respiratory tract infection. Several authors have reported a severe clinical course after RSV infections in infants and children with primary and acquired immunodeficiencies. Environmental prophylaxis is essential in order to reduce the infection during the epidemic season in hospitalized immunocompromised infants. Prophylaxis with palivizumab, a humanized monoclonal antibody against the RSV F protein, is currently recommended in high-risk infants born prematurely, with chronic lung disease or congenital heart disease. Currently however the prophylaxis is not routinely recommended in infants with primary immunodeficiency, although some authors propose the extension of prophylaxis to this high risk population. PMID:25089282

  15. Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome

    PubMed Central

    Kotlarz, Daniel; Ziętara, Natalia; Uzel, Gulbu; Weidemann, Thomas; Braun, Christian J.; Diestelhorst, Jana; Krawitz, Peter M.; Robinson, Peter N.; Hecht, Jochen; Puchałka, Jacek; Gertz, E. Michael; Schäffer, Alejandro A.; Lawrence, Monica G.; Kardava, Lela; Pfeifer, Dietmar; Baumann, Ulrich; Pfister, Eva-Doreen; Hanson, Eric P.; Schambach, Axel; Jacobs, Roland; Kreipe, Hans; Moir, Susan; Milner, Joshua D.; Schwille, Petra; Mundlos, Stefan

    2013-01-01

    Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21RArg201Leu mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21–induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children. PMID:23440042

  16. Primary Immunodeficiency Diseases: An Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency

    PubMed Central

    Al-Herz, Waleed; Bousfiha, Aziz; Casanova, Jean-Laurent; Chapel, Helen; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Fischer, Alain; Franco, Jose Luis; Geha, Raif S.; Hammarström, Lennart; Nonoyama, Shigeaki; Notarangelo, Luigi Daniele; Ochs, Hans Dieter; Puck, Jennifer M.; Roifman, Chaim M.; Seger, Reinhard; Tang, Mimi L. K.

    2011-01-01

    We report the updated classification of primary immunodeficiency diseases, compiled by the ad hoc Expert Committee of the International Union of Immunological Societies. As compared to the previous edition, more than 15 novel disease entities have been added in the updated version. For each disorders, the key clinical and laboratory features are provided. This updated classification is meant to help in the diagnostic approach to patients with these diseases. PMID:22566844

  17. Inflammatory bowel disease: is it a primary immunodeficiency?

    PubMed

    Glocker, Erik; Grimbacher, Bodo

    2012-01-01

    Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease are chronic and relapsing conditions, characterized by abdominal pain, diarrhea, bleeding and malabsorption. IBD has been considered a hyperinflammatory state due to disturbed interactions between the immune system and the commensal bacterial flora of the gut. However, there is evidence that Crohn's disease might be the consequence of a reduced release of pro-inflammatory cytokines and an impaired acute inflammatory response, thereby suggesting that IBD might be an immunodeficiency rather than an excessive inflammatory reaction. This theory has been supported by observations in patients with primary immunodeficiencies such as the Wiskott-Aldrich syndrome and IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). In contrary, defects in the anti-inflammatory down-regulation of the immune response as they are seen in patients with Mendelian defects in the IL10 signaling pathway support the hyper-inflammatory theory. In this review, we describe and discuss primary immunodeficiencies associated with IBD and show that the bowel is a highly sensitive indicator of dysregulations, making IBD a model disease to study and identify key regulators required to balance the human mucosal immune system. PMID:21997382

  18. Primary immunodeficiency diseases: dissectors of the immune system.

    PubMed

    Buckley, Rebecca H

    2002-07-01

    The past 50 years have seen enormous progress in this field. An unknown concept until 1952, there are now more than 100 different primary immunodeficiency syndromes in the world's literature. Each novel syndrome has shed new insight into the workings of the immune system, dissecting its multiple parts into unique functioning components. This has been especially true over the past decade, as the molecular bases of approximately 40 of these diseases have been identified in rapid succession. Advances in the treatment of these diseases have also been impressive. Antibody replacement has been improved greatly by the development of human immunoglobulin preparations that can be safely administered by the intravenous route, and cytokine and humanized anticytokine therapies are now possible through recombinant technologies. The ability to achieve life-saving immune reconstitution of patients with lethal severe combined immunodeficiency by administering rigorously T-cell-depleted allogeneic related haploidentical bone marrow stem cells has extended this option to virtually all such infants, if diagnosed before untreatable infections develop. Finally, the past 3 years have witnessed the first truly successful gene therapy. The impressive results in X-linked severe combined immunodeficiency offer hope that this approach can be extended to many more diseases in the future. PMID:12190932

  19. Efficacy and safety of Gammaplex(®) 5% in children and adolescents with primary immunodeficiency diseases.

    PubMed

    Melamed, I R; Gupta, S; Stratford Bobbitt, M; Hyland, N; Moy, J N

    2016-05-01

    This open-label multi-centre study evaluated Gammaplex(®) 5%, a human intravenous immunoglobulin (IVIG) 5% liquid, in 25 children and adolescent patients (aged 3-16 years) with primary immunodeficiency diseases (PIDs). Subjects received Gammaplex 5% (at doses of 300-800 mg/kg/infusion) for 12 months, with a 3-month follow-up. The primary efficacy end-point was the incidence of serious acute bacterial infections (SABIs) during the 12-month treatment period. Secondary objectives assessed safety and tolerability. Nineteen males and six females were treated using the same infusion schedule as their prior IVIG treatment (14 and 11 subjects on 21- and 28-day dosing schedules, respectively). Two SABIs of pneumonia were reported, resulting in an annual SABI event rate of 0·09 [upper one-sided 99% confidence interval (CI) = 0·36]. Twenty-one subjects (84%) experienced ≥ 1 infection during the study, with a median infective episode per subject/year of 3·08 (range = 0-10·4). Sixteen subjects (64%) missed ≥ 1 day of nursery or school because of infection or other illness. All trough immunoglobulin G levels exceeded 7·00 g/l after 15 weeks (mean = 9·69 g/l; range = 7·04-15·35 g/l). Product-related adverse events occurred in 14 subjects (56%); none were serious. Of 368 total infusions, 97 (26%) were associated temporally with an adverse event (≤ 72 h after infusion), regardless of causality. Laboratory test results and adverse-reaction data showed no evidence of product-related haemolysis or thromboembolic events. These data demonstrate that Gammaplex 5% is effective in preventing SABIs and well tolerated in children and adolescents with PID. PMID:26696596

  20. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus

    PubMed Central

    Li, Feng-Yen; Chaigne-Delalande, Benjamin; Su, Helen; Uzel, Gulbu; Matthews, Helen

    2014-01-01

    Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that infects and persists in 95% of adults worldwide and has the potential to cause fatal disease, especially lymphoma, in immunocompromised hosts. Primary immunodeficiencies (PIDs) that predispose to EBV-associated malignancies have provided novel insights into the molecular mechanisms of immune defense against EBV. We have recently characterized a novel PID now named “X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia” (XMEN) disease characterized by loss-of-function mutations in the gene encoding magnesium transporter 1 (MAGT1), chronic high-level EBV with increased EBV-infected B cells, and heightened susceptibility to EBV-associated lymphomas. The genetic etiology of XMEN disease has revealed an unexpected quantitative role for intracellular free magnesium in immune functions and has led to novel diagnostic and therapeutic strategies. Here, we review the clinical presentation, genetic mutation spectrum, molecular mechanisms of pathogenesis, and diagnostic and therapeutic considerations for this previously unrecognized disease. PMID:24550228

  1. Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency.

    PubMed

    Cipe, Funda Erol; Aydogmus, Cigdem; Babayigit Hocaoglu, Arzu; Kilic, Merve; Kaya, Gul Demet; Yilmaz Gulec, Elif

    2014-01-01

    Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomologous end joining pathways of DNA repair mechanisms have been identified as responsible for radiosensitive SCID. Here, we present a 3-year-old girl patient with severe growth retardation, bird-like face, recurrent perianal abscess, pancytopenia, and polydactyly. Firstly, she was thought as Fanconi anemia and spontaneous DNA breaks were seen on chromosomal analysis. After that DEB test was found to be normal and Fanconi anemia was excluded. Because of that she had low IgG and IgA levels, normal IgM level, and absence of B cells in peripheral blood; she was considered as primary immunodeficiency, Nijmegen breakage syndrome. A mutation in NBS1 gene was not found; then Cernunnos/XLF deficiency was investigated due to clinical similarities with previously reported cases. Homozygous mutation in Cernunnos/XLF gene (NHEJ1) was identified. She is now on regular IVIG prophylaxis and has no new infection. Fully matched donor screening is in progress for bone marrow transplantation which is curative treatment of the disease. In conclusion, the patients with microcephaly, bird-like face, and severe growth retardation should be evaluated for hypogammaglobulinemia and primary immunodeficiency diseases. PMID:24511403

  2. Cernunnos/XLF Deficiency: A Syndromic Primary Immunodeficiency

    PubMed Central

    Çipe, Funda Erol; Aydogmus, Cigdem; Babayigit Hocaoglu, Arzu; Kilic, Merve; Kaya, Gul Demet; Yilmaz Gulec, Elif

    2014-01-01

    Artemis, DNA ligase IV, DNA protein kinase catalytic subunit, and Cernunnos/XLF genes in nonhomologous end joining pathways of DNA repair mechanisms have been identified as responsible for radiosensitive SCID. Here, we present a 3-year-old girl patient with severe growth retardation, bird-like face, recurrent perianal abscess, pancytopenia, and polydactyly. Firstly, she was thought as Fanconi anemia and spontaneous DNA breaks were seen on chromosomal analysis. After that DEB test was found to be normal and Fanconi anemia was excluded. Because of that she had low IgG and IgA levels, normal IgM level, and absence of B cells in peripheral blood; she was considered as primary immunodeficiency, Nijmegen breakage syndrome. A mutation in NBS1 gene was not found; then Cernunnos/XLF deficiency was investigated due to clinical similarities with previously reported cases. Homozygous mutation in Cernunnos/XLF gene (NHEJ1) was identified. She is now on regular IVIG prophylaxis and has no new infection. Fully matched donor screening is in progress for bone marrow transplantation which is curative treatment of the disease. In conclusion, the patients with microcephaly, bird-like face, and severe growth retardation should be evaluated for hypogammaglobulinemia and primary immunodeficiency diseases. PMID:24511403

  3. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies

    PubMed Central

    Conley, Mary Ellen; Seligman, Stephen J.; Abel, Laurent; Notarangelo, Luigi D.

    2014-01-01

    Can genetic and clinical findings made in a single patient be considered sufficient to establish a causal relationship between genotype and phenotype? We report that up to 49 of the 232 monogenic etiologies (21%) of human primary immunodeficiencies (PIDs) were initially reported in single patients. The ability to incriminate single-gene inborn errors in immunodeficient patients results from the relative ease in validating the disease-causing role of the genotype by in-depth mechanistic studies demonstrating the structural and functional consequences of the mutations using blood samples. The candidate genotype can be causally connected to a clinical phenotype using cellular (leukocytes) or molecular (plasma) substrates. The recent advent of next generation sequencing (NGS), with whole exome and whole genome sequencing, induced pluripotent stem cell (iPSC) technology, and gene editing technologies—including in particular the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology—offer new and exciting possibilities for the genetic exploration of single patients not only in hematology and immunology but also in other fields. We propose three criteria for deciding if the clinical and experimental data suffice to establish a causal relationship based on only one case. The patient’s candidate genotype must not occur in individuals without the clinical phenotype. Experimental studies must indicate that the genetic variant impairs, destroys, or alters the expression or function of the gene product (or two genetic variants for compound heterozygosity). The causal relationship between the candidate genotype and the clinical phenotype must be confirmed via a relevant cellular phenotype, or by default via a relevant animal phenotype. When supported by satisfaction of rigorous criteria, the report of single patient–based discovery of Mendelian disorders should be encouraged, as it can provide the first step in the understanding of a group of

  4. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies.

    PubMed

    Casanova, Jean-Laurent; Conley, Mary Ellen; Seligman, Stephen J; Abel, Laurent; Notarangelo, Luigi D

    2014-10-20

    Can genetic and clinical findings made in a single patient be considered sufficient to establish a causal relationship between genotype and phenotype? We report that up to 49 of the 232 monogenic etiologies (21%) of human primary immunodeficiencies (PIDs) were initially reported in single patients. The ability to incriminate single-gene inborn errors in immunodeficient patients results from the relative ease in validating the disease-causing role of the genotype by in-depth mechanistic studies demonstrating the structural and functional consequences of the mutations using blood samples. The candidate genotype can be causally connected to a clinical phenotype using cellular (leukocytes) or molecular (plasma) substrates. The recent advent of next generation sequencing (NGS), with whole exome and whole genome sequencing, induced pluripotent stem cell (iPSC) technology, and gene editing technologies-including in particular the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology-offer new and exciting possibilities for the genetic exploration of single patients not only in hematology and immunology but also in other fields. We propose three criteria for deciding if the clinical and experimental data suffice to establish a causal relationship based on only one case. The patient's candidate genotype must not occur in individuals without the clinical phenotype. Experimental studies must indicate that the genetic variant impairs, destroys, or alters the expression or function of the gene product (or two genetic variants for compound heterozygosity). The causal relationship between the candidate genotype and the clinical phenotype must be confirmed via a relevant cellular phenotype, or by default via a relevant animal phenotype. When supported by satisfaction of rigorous criteria, the report of single patient-based discovery of Mendelian disorders should be encouraged, as it can provide the first step in the understanding of a group of human

  5. Placental transfer of maternally-derived IgA precludes the use of guthrie card eluates as a screening tool for primary immunodeficiency diseases.

    PubMed

    Borte, Stephan; Janzi, Magdalena; Pan-Hammarström, Qiang; von Döbeln, Ulrika; Nordvall, Lennart; Winiarski, Jacek; Fasth, Anders; Hammarström, Lennart

    2012-01-01

    There is a need for neonatal screening tools to improve the long-term clinical outcome of patients with primary immunodeficiency diseases (PID). Recently, a PCR-based screening method for both TRECs and KRECs using Guthrie card samples has been developed. However, the applicability of these excision circle assays is limited to patients with severe T or B cell lymphopenia (SCID, XLA and A-T), whereas the most common forms of PID are not detected. Absence of serum IgA is seen in a major fraction of patients with immunological defects. As serum IgA in newborns is considered to be of fetal origin, eluates from routinely collected dried blood spot samples might thus be suitable for identification of children with PID. To assess the applicability of such screening assays, stored Guthrie card samples were obtained from 47 patients with various forms of primary immunodeficiency diseases (SCID, XLA, A-T, HIGM and IgAD), 20 individuals with normal serum IgA levels born to IgA-deficient mothers and 51 matched healthy newborns. Surprisingly, normal serum IgA levels were found in all SCID, XLA, A-T and HIGM patients and, additionally, in all those IgAD patients born to IgA-sufficient mothers. Conversely, no serum IgA was found in any of the 16 IgAD patients born by IgA-deficient mothers. Moreover, half of the IgA-sufficient individuals born by IgA-deficient mothers also lacked IgA at birth whereas no IgA-deficient individuals were found among the controls. IgA in neonatal dried blood samples thus appears to be of both maternal and fetal origin and precludes its use as a reliable marker for neonatal screening of primary immunodeficiency diseases. PMID:22916257

  6. Gene therapy for primary immunodeficiencies: current status and future prospects.

    PubMed

    Qasim, Waseem; Gennery, Andrew R

    2014-06-01

    Gene therapy using autologous haematopoietic stem cells offers a valuable treatment option for patients with primary immunodeficiencies who do not have access to an HLA-matched donor, although such treatments have not been without their problems. This review details gene therapy trials for X-linked and adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). X-linked SCID was chosen for gene therapy because of previous 'natural' genetic correction through a reversion event in a single lymphoid precursor, demonstrating limited thymopoiesis and restricted T-lymphocyte receptor repertoire, showing selective advantage of progenitors possessing the wild-type gene. In early studies, patients were treated with long terminal repeats-intact gamma-retroviral vectors, without additional chemotherapy. Early results demonstrated gene-transduced cells, sustained thymopoiesis, and a diverse T-lymphocyte repertoire with normal function. Serious adverse effects were subsequently reported in 5 of 20 patients, with T-lymphocyte leukaemia developing, secondary to the viral vector integrating adjacent to a known oncogene. New trials using self-inactivating gamma-retroviral vectors are progressing. Trials for ADA-SCID using gamma-retroviral vectors have been successful, with no similar serious adverse effects reported; trials using lentiviral vectors are in progress. Patients with WAS and CGD treated with early gamma-retroviral vectors have developed similar lymphoproliferative adverse effects to those seen in X-SCID--current trials are using new-generation vectors. Targeted gene insertion using homologous recombination of corrected gene sequences by cellular DNA repair pathways following targeted DNA breakage will improve efficacy and safety of gene therapy. A number of new techniques are discussed. PMID:24848753

  7. Allogeneic Bone Marrow Transplantation in Patients With Primary Immunodeficiencies

    ClinicalTrials.gov

    2009-10-14

    Immunologic Deficiency Syndromes; Chediak-Higashi Syndrome; Common Variable Immunodeficiency; Graft Versus Host Disease; X-Linked Lymphoproliferative Syndrome; Familial Erythrophagocytic Lymphohistiocytosis; Hemophagocytic Lymphohistiocytosis; X-linked Agammaglobulinemia; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Hyper IgM Syndrome; Severe Combined Immunodeficiency; Leukocyte Adhesion Deficiency Syndrome; Virus-Associated Hemophagocytic Syndrome

  8. 7th International Immunoglobulin Conference: Immunodeficiencies.

    PubMed

    Schmidt, R E; Ochs, H D

    2014-12-01

    Most primary immunodeficiency disorders (PID) are the result of single gene defects. Based on this fact, more than 240 different entities have been identified. Those PIDs with predominant antibody deficiency are treated with immunoglobulin (Ig) replacement therapy. This review focuses on the diagnosis, clinical characteristics and treatment of patients suffering from PID, or secondary immunodeficiency disorders (SID) caused, for instance, by irradiation, immunosuppressive drugs or thymectomy. Common variable immunodeficiency (CVID) is the most commonly diagnosed and least understood form of PID, with a heterogeneous range of symptoms and genotypes, requiring individualized treatment plans. This includes adjusting the dose and treatment interval, administrating Ig by intravenous or subcutaneous injection by either pump or push, and finally deciding which treatment options are best for a given patient. Ig therapy can also be used to treat immunodeficiencies resulting from lymphoproliferative and autoimmune diseases or immunosuppression following organ transplantation; however, there is an urgent need for research in this field. Accurate and early diagnosis of PID is important to ensure that optimal treatment is started early to maintain the patient's health. Detailed patient registries have been established to increase awareness of PID, as well as provide a valuable resource for further research. PMID:25546741

  9. Diagnosis and Treatment of Gastrointestinal Disorders in Patients With Primary Immunodeficiency

    PubMed Central

    AGARWAL, SHRADHA; MAYER, LLOYD

    2013-01-01

    Gastrointestinal disorders such as chronic or acute diarrhea, malabsorption, abdominal pain, and inflammatory bowel diseases can indicate immune deficiency. The gastrointestinal tract is the largest lymphoid organ in the body, so it is not surprising that intestinal diseases are common among immunodeficient patients. Gastroenterologists therefore must be able to diagnose and treat patients with primary immunodeficiency. Immune-related gastrointestinal diseases can be classified as those that develop primarily via autoimmunity, infection, an inflammatory response, or malignancy. Immunodeficient and immunocompetent patients with gastrointestinal diseases present with similar symptoms. However, intestinal biopsy specimens from immunodeficient patients often have distinct histologic features, and these patients often fail to respond to conventional therapies. Therefore, early recognition of symptoms and referral to an immunologist for a basic immune evaluation is required to select appropriate treatments. Therapies for primary immunodeficiency comprise immunoglobulin replacement, antibiotics, and, in severe cases, bone marrow transplantation. Treatment of immunodeficient patients with concomitant gastrointestinal disease can be challenging, and therapy with immunomodulators often is required for severe disease. This review aims to guide gastroenterologists in the diagnosis and treatment of patients with primary immunodeficiency. PMID:23501398

  10. Epstein-Barr and human immunodeficiency viruses in acquired immunodeficiency syndrome-related primary central nervous system lymphoma.

    PubMed Central

    Morgello, S.

    1992-01-01

    The prevalence of Epstein-Barr virus (EBV) and human immunodeficiency virus (HIV) in acquired immunodeficiency syndrome (AIDS)-related primary central nervous system (CNS) lymphoma was examined. Deoxyribonucleic acid (DNA) extracted from 12 formalin-fixed, paraffin-embedded tumors was used as substrate for the polymerase chain reaction (PCR). Targets for amplification were the EBNA-1 region of EBV, the gag region of HIV, and a single copy cellular sequence as a control. The cases studied were autopsy and surgical specimens collected between the years 1985 and 1989. By the working formulation for non-Hodgkin's lymphomas, five had large cell, four had mixed large and small cleaved cell, two had small cleaved cell, and one had an unclassified histology. Epstein-Barr virus was detected in 6 of 12 tumors studied. Human immunodeficiency virus was not detected in any of the tumors. The presence of EBV was not correlated with any particular histologic tumor type. It is concluded that EBV, not HIV, can be detected in a large percentage (50%) of AIDS-related primary central nervous system (CNS) lymphomas. This viral association may be significant in light of the demonstrated ability of EBV to induce lymphoid tumors in experimental mammalian systems. Images Figure 1 Figure 2 PMID:1323221

  11. Hematopoietic Stem Cell Transplantation for Primary Immunodeficiencies By Elizabeth Kang and Andrew Gennery

    PubMed Central

    Kang, Elizabeth; Gennery, Andrew

    2014-01-01

    Allogeneic Hematopoietic Stem Cell Transplantation has been shown to be curative for well described as well as newly discovered immunodeficiencies. However it is difficulty to define a universal transplant regimen given the rarity of these disorders and the varied pathophysiology these disorders encompass. This review will discuss those primary immunodeficiencies most commonly treated by hematopoietic stem cell transplant and describe the transplant issues specific to these disorders. PMID:25459185

  12. Efficacy and Safety of a New 20% Immunoglobulin Preparation for Subcutaneous Administration, IgPro20, in Patients With Primary Immunodeficiency

    PubMed Central

    Fasano, Mary B.; Spector, Sheldon; Wasserman, Richard L.; Melamed, Isaac; Rojavin, Mikhail A.; Zenker, Othmar; Orange, Jordan S.

    2010-01-01

    Subcutaneous human IgG (SCIG) therapy in primary immunodeficiency (PID) offers sustained IgG levels throughout the dosing cycle and fewer adverse events (AEs) compared to intravenous immunoglobulin (IVIG). A phase I study showed good local tolerability of IgPro20, a new 20% liquid SCIG stabilized with L-proline. A prospective, open-label, multicenter, single-arm, phase III study evaluated the efficacy and safety of IgPro20 in patients with PID over 15 months. Forty-nine patients (5–72 years) previously treated with IVIG received weekly subcutaneous infusions of IgPro20. The mean serum IgG level was 12.5 g/L. No serious bacterial infections were reported. There were 96 nonserious infections (rate 2.76/patient per year). The rate of days missed from work/school was 2.06/patient per year, and the rate of hospitalization was 0.2/patient per year. Ninety-nine percent of AEs were mild or moderate. No serious, IgPro20-related AEs were reported. IgPro20 effectively protected patients with PID against infections and maintained serum IgG levels without causing unexpected AEs. PMID:20454851

  13. A Phenotypic Approach for IUIS PID Classification and Diagnosis: Guidelines for Clinicians at the Bedside

    PubMed Central

    Jeddane, Leïla; Ailal, Fatima; Al Herz, Waleed; Conley, Mary Ellen; Cunningham-Rundles, Charlotte; Etzioni, Amos; Fischer, Alain; Franco, Jose Luis; Geha, Raif S.; Hammarström, Lennart; Nonoyama, Shigeaki; Ochs, Hans D.; Roifman, Chaim M.; Seger, Reinhard; Tang, Mimi L. K.; Puck, Jennifer M.; Chapel, Helen; Notarangelo, Luigi D.; Casanova, Jean-Laurent

    2014-01-01

    The number of genetically defined Primary Immunodeficiency Diseases (PID) has increased exponentially, especially in the past decade. The biennial classification published by the IUIS PID expert committee is therefore quickly expanding, providing valuable information regarding the disease-causing genotypes, the immunological anomalies, and the associated clinical features of PIDs. These are grouped in eight, somewhat overlapping, categories of immune dysfunction. However, based on this immunological classification, the diagnosis of a specific PID from the clinician’s observation of an individual clinical and/or immunological phenotype remains difficult, especially for non-PID specialists. The purpose of this work is to suggest a phenotypic classification that forms the basis for diagnostic trees, leading the physician to particular groups of PIDs, starting from clinical features and combining routine immunological investigations along the way.We present 8 colored diagnostic figures that correspond to the 8 PID groups in the IUIS Classification, including all the PIDs cited in the 2011 update of the IUIS classification and most of those reported since. PMID:23657403

  14. The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis

    PubMed Central

    Bode, Sebastian FN; Ammann, Sandra; Al-Herz, Waleed; Bataneant, Mihaela; Dvorak, Christopher C; Gehring, Stephan; Gennery, Andrew; Gilmour, Kimberly C; Gonzalez-Granado, Luis I; Groß-Wieltsch, Ute; Ifversen, Marianne; Lingman-Framme, Jenny; Matthes-Martin, Susanne; Mesters, Rolf; Meyts, Isabelle; van Montfrans, Joris M; Schmid, Jana Pachlopnik; Pai, Sung-Yun; Soler-Palacin, Pere; Schuermann, Uta; Schuster, Volker; Seidel, Markus G.; Speckmann, Carsten; Stepensky, Polina; Sykora, Karl-Walter; Tesi, Bianca; Vraetz, Thomas; Waruiru, Catherine; Bryceson, Yenan T.; Moshous, Despina; Lehmberg, Kai; Jordan, Michael B; Ehl, Stephan

    2015-01-01

    Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with <100/μL T cells, 18 had partial T-cell deficiencies; episodes of hemophagocytic lymphohistiocytosis were mostly associated with viral infections. Twenty-two patients had chronic granulomatous disease with hemophagocytic episodes mainly associated with bacterial infections. Compared to patients with cytotoxicity defects, patients with T-cell deficiencies had lower levels of soluble CD25 and higher ferritin concentrations. Other criteria for hemophagocytoc lymphohistiocytosis were not discriminative. Thus: (i) a hemophagocytic inflammatory syndrome fulfilling criteria for hemophagocytic lymphohistiocytosis can be the initial manifestation of primary immunodeficiencies; (ii) this syndrome can develop despite severe deficiency of T and NK cells, implying that the pathophysiology is distinct and not appropriately described as “lympho”-histiocytosis in these patients; and (iii) current criteria for

  15. Long-term outcomes of fludarabine, melphalan and antithymocyte globulin as reduced-intensity conditioning regimen for allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiency disorders: a prospective single center study.

    PubMed

    Hamidieh, A A; Behfar, M; Pourpak, Z; Faghihi-Kashani, S; Fazlollahi, M R; Hosseini, A S; Movahedi, M; Mozafari, M; Moin, M; Ghavamzadeh, A

    2016-02-01

    Reduced-intensity conditioning (RIC) has offered many primary immunodeficiency disorder (PID) patients who are ineligible for myeloablative regimens a chance of cure. However, the beneficial role of RIC was questioned following reports suggesting higher chance of rejection and lower symptom resolution rate in mixed chimerism settings. Forty-five children affected by PIDs with a median age of 21 months underwent allogeneic hematopoietic stem cell transplantation in our institute from 2007 to 2013. All patients received an identical RIC regimen. Forty-one patients had successful primary engraftment (91%). Of the successful engraftments, 80% (n=33) had stable full donor chimerism at last contact. Overall, eleven transplant-related mortalities were reported including five patients due to sepsis, three children due to grade IV acute GvHD, two due to chronic GvHD and one patient due to sepsis after primary graft failure. The median post-transplantation follow-up of deceased patients was 55 days. Five-year overall survival and disease-free survival was 75.6% and 68.89%, respectively. All surviving patients with successful engraftment became disease free, regardless of having full or mixed chimerism. Our study suggests that RIC regimen provides satisfactory rates of successful engraftment and full chimerism. Furthermore, patients with mixed chimerism were stable in long-term follow-up and this chimerism status offered the potential to resolve symptoms of immunodeficiency. PMID:26595073

  16. Human Immunodeficiency Virus Type 1 Coat Protein Neurotoxicity Mediated by Nitric Oxide in Primary Cortical Cultures

    NASA Astrophysics Data System (ADS)

    Dawson, Valina L.; Dawson, Ted M.; Uhl, George R.; Snyder, Solomon H.

    1993-04-01

    The human immunodeficiency virus type 1 coat protein, gp120, kills neurons in primary cortical cultures at low picomolar concentrations. The toxicity requires external glutamate and calcium and is blocked by glutamate receptor antagonists. Nitric oxide (NO) contributes to gp120 toxicity, since nitroarginine, an inhibitor of NO synthase, prevents toxicity as does deletion of arginine from the incubation medium and hemoglobin, which binds NO. Superoxide dismutase also attenuates toxicity, implying a role for superoxide anions.

  17. Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency.

    PubMed

    Elgizouli, M; Lowe, D M; Speckmann, C; Schubert, D; Hülsdünker, J; Eskandarian, Z; Dudek, A; Schmitt-Graeff, A; Wanders, J; Jørgensen, S F; Fevang, B; Salzer, U; Nieters, A; Burns, S; Grimbacher, B

    2016-02-01

    The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain-of-function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kδ syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype. PMID:26437962

  18. Single-Center Experience of Unrelated and Haploidentical Stem Cell Transplantation with TCRαβ and CD19 Depletion in Children with Primary Immunodeficiency Syndromes.

    PubMed

    Balashov, Dmitry; Shcherbina, Anna; Maschan, Michael; Trakhtman, Pavel; Skvortsova, Yulia; Shelikhova, Larisa; Laberko, Alexandra; Livshits, Anna; Novichkova, Galina; Maschan, Alexei

    2015-11-01

    The transplantation of stem cells from a matched unrelated donor (MUD) or a haploidentical mismatched related donor (MMRD) is a widely used variant of curative treatment for patients with primary immunodeficiency (PID). Currently, different strategies are used to reduce the risk of post-transplant complications and enhance immune reconstitution. We report the preliminary results of MUD and MMRD transplantation with TCRαβ/CD19 depletion in patients with PID (trial registered at www.clinicaltrials.gov as NCT02327351). Thirty-seven PID patients (median age, 2.6 years; range, .2 to 17) were transplanted from MUDs (n = 27) or haploidentical MMRDs (n = 10) after TCRαβ(+)/CD19(+) graft depletion. The median numbers of CD34(+) and TCRαβ(+) cells in the graft were 11.7 × 10(6)/kg and 10.6 × 10(3)/kg, respectively. Acute graft-versus-host disease (GVHD) was observed in 8 patients (22%), without a statistically significant difference between MUDs and MMRDs; 7 of these patients had grade II acute GVHD and responded to first-line therapy, whereas 1 patient had grade IV acute GVHD with transformation to extensive chronic GVHD. Primary and secondary graft failure (nonengraftment or rejection) was observed in 10 patients (27%), 9 of whom were treated with 1 alkylating agent in the conditioning regimen. All these patients were successfully retransplanted with different rescue protocols. Preliminary data on immune reconstitution were very encouraging. Most patients had significant numbers of T lymphocytes detected on the first assessment (day +30) and more than 500 T cells/μL, on day +120. Based on our preliminary data, no significant difference was seen between MMRD and MUD hematopoietic stem cell transplantation (HSCT). With a median follow-up period of 15 months, the cumulative probabilities of overall patient survival and transplant-related mortality were 96.7% and 3.3%, respectively. Based on the results, the ability to control the main post

  19. Gene transfer into hematopoietic stem cells as treatment for primary immunodeficiency diseases.

    PubMed

    Candotti, Fabio

    2014-04-01

    Gene transfer into the hematopoietic stem cell has shown curative potential for a variety of hematological disorders. Primary immunodeficiency diseases have led to the way in this field of gene therapy as an example and a model. Clinical results from the past 15 years have shown that significant improvement and even cure can be achieved for diseases such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic granulomatous disease and Wiskott-Aldrich syndrome. Unfortunately, with the initial clear clinical benefits, the first serious complications of gene therapy have also occurred. In a significant number of patients treated using vectors based on murine gamma-retroviruses and carrying powerful viral enhancer elements, insertional oncogenesis events have resulted in acute leukemias that, in some cases, have had fatal outcomes. These serious adverse events have sparked a revision of the assessment of risks and benefits of integrating gene transfer for hematological diseases and prompted the development and application of new generations of viral vectors with recognized superior safety characteristics. This review summarizes the clinical experience of gene therapy for primary immunodeficiencies and discusses the likely avenues of progress in the future development of this expanding field of clinical investigations. PMID:24488786

  20. Primary Effusion Lymphoma (PEL)-Like Lymphoma in a Child With Congenital Immunodeficiency.

    PubMed

    Lam, Grace K S; Abdelhaleem, Mohamed; Somers, Gino R; Roifman, Chaim; Read, Stanley; Abla, Oussama

    2016-09-01

    Primary effusion lymphoma (PEL) is a rare lymphoma that occurs more frequently in immunocompromised adults and has a poor survival. We report a 9-year-old female with combined immunodeficiency with an Epstein-Barr virus positive/human herpes virus 8 negative PEL-like lymphoma. The treatment with systemic chemotherapy for non-Hodgkin lymphoma, zidovudine, and interferon-α failed to control disease progression. This is the first reported pediatric case of PEL-like lymphoma. Increased diagnostic awareness and more effective treatment strategies are needed for this rare lymphoma. PMID:27186682

  1. Intravenous immunoglobulin induces proliferation and immunoglobulin synthesis from B cells of patients with common variable immunodeficiency: a mechanism underlying the beneficial effect of IVIg in primary immunodeficiencies.

    PubMed

    Bayry, Jagadeesh; Fournier, Emilie M; Maddur, Mohan S; Vani, Janakiraman; Wootla, Bharath; Sibéril, Sophie; Dimitrov, Jordan D; Lacroix-Desmazes, Sébastien; Berdah, Mikael; Crabol, Yoann; Oksenhendler, Eric; Lévy, Yves; Mouthon, Luc; Sautès-Fridman, Catherine; Hermine, Olivier; Kaveri, Srini V

    2011-02-01

    Common variable immunodeficiency (CVID) is associated with low serum immunoglobulin concentrations and an increased susceptibility to infections and autoimmune diseases. The treatment of choice for CVID patients is replacement intravenous immunoglobulin (IVIg) therapy. IVIg has been beneficial in preventing or alleviating the severity of infections and autoimmune and inflammatory process in majority of CVID patients. Although the mechanisms of action of IVIg given as 'therapeutic high dose' in patients with autoimmune diseases are well studied, the underlying mechanisms of beneficial effects of IVIg in primary immunodeficiencies are not completely understood. Therefore we investigated the effect of 'replacement dose' of IVIg by probing its action on B cells from CVID patients. We demonstrate that IVIg at low doses induces proliferation and immunoglobulin synthesis from B cells of CVID patients. Interestingly, B cell stimulation by IVIg is not associated with induction of B cell effector cytokine IFN-γ and of transcription factor T-bet. Together, our results indicate that in some CVID patients, IVIg rectifies the defective signaling of B cells normally provided by T cells and delivers T-independent signaling for B cells to proliferate. IVIg 'replacement therapy' in primary immunodeficiencies is therefore not a merepassive transfer of antibodies to prevent exclusively the recurrent infections; rather it has an active role in regulating autoimmune and inflammatory responses through modulating B cell functions and thus imposing dynamic equilibrium of the immune system. PMID:20970960

  2. Primary immunodeficiencies worldwide: an updated overview from the Jeffrey Modell Centers Global Network.

    PubMed

    Modell, Vicki; Quinn, Jessica; Orange, Jordan; Notarangelo, Luigi D; Modell, Fred

    2016-06-01

    Primary immunodeficiencies (PI) are defects of the immune system that cause severe, sometimes life-threatening, infections if not diagnosed and treated appropriately. Many patients with PI are undiagnosed, under-diagnosed, or misdiagnosed. To raise awareness and assure earliest diagnosis, appropriate treatment, and proper care management, the Jeffrey Modell Foundation (JMF) implemented a physician education and public awareness program beginning in 2003. Data are requested annually from physician experts within the Jeffrey Modell Centers Network (JMCN), consisting of 602 expert physicians, at 253 academic institutions, in 206 cities, and 84 countries spanning six continents. Center Directors reported on patients' specific PI defects and treatment modalities including immunoglobulins, transplantation, and gene therapy as well as data on gender and age. Center Directors also provided physician-reported patient outcomes as well as pre- and post-diagnosis differences. Costs were assigned to these factors. In collaboration with the Network, JMF advocated, funded, and implemented population-based newborn screening for severe combined immunodeficiency and T cell lymphopenia, covering 96.2 % of all newborns in the US. Finally, 21 JMF Centers participated in a polio surveillance study of patients with PI who either received or have been exposed to the oral polio vaccine. These initiatives have led to an overall better understanding of the immune system and will continue to improve quality of life for those with PI. PMID:26802037

  3. Rare Mendelian Primary Immunodeficiency diseases associated to impaired NF-κB signaling

    PubMed Central

    Paciolla, Mariateresa; Pescatore, Alessandra; Conte, Matilde Immacolata; Esposito, Elio; Incoronato, Mariarosaria; Lioi, Maria Brigida; Fusco, Francesca; Ursini, Matilde Valeria

    2015-01-01

    Mendelian Primary Immunodeficiency Diseases (MPIDs) are rare disorders affecting distinct constituents of the innate and adaptive immune system. Although they are genetically heterogeneous a substantial group of MPIDs is due to mutations in genes affecting the NF-κB transcription pathway, essential for cell proliferation, cell survival, and involved in innate immunity and in inflammation. Many of these genes encode for crucial regulatory components of NF-κB pathway and their mutations are associated with immunological and developmental signs somehow overlapping in patients with MPIDs. At present nine different MPIDs listed in the OMIM are caused by mutations in at least nine different genes strictly involved in the NF-κB pathway that result in defects in immune responses. We will report here on the distinct function of each causative gene, on the impaired NF-κB step and more in general on the molecular mechanisms underlining the pathogenesis of the disease. Overall, the MPIDs affecting NF-κB signalosome require a careful integrated diagnosis and appropriate genetic tests to be molecularly identified. Their discovery at an ever-increasing rate will help to establish common therapeutic strategy for a subclass of immunodeficient patients. PMID:25764117

  4. Pyoderma Vegetans: A Case Report in a Child Suspected to Primary Immunodeficiency and Review of the Literature

    PubMed Central

    Mansouri, Mahboubeh; Rakhshan, Azadeh; Shahidi-Dadras, Mohammad; Karimi, Abdollah; Alavi, Samin

    2015-01-01

    Pyoderma vegetans (PV) is a rare inflammatory disorder characterized by vegetating pustules and plaques affecting the skin and mucosal membranes. It is believed that this entity is mostly associated with inflammatory bowel disease (IBD), chronic malnutrition, human immunodeficiency virus (HIV), malignancies, and other immunocompromised states. Pyoderma vegetans occurs more commonly in young and middle-aged adults. There is no sex predilection for this entity. The lesions could heal spontaneously, but usually recur and become chronic. Our patient was an 11-year-old girl suspected to have primary combined immunodeficiency complicated by chronic recurrent vegetating pustular lesions on the face and postauricular area since one year of age. The histological features of the lesions were consistent with pyoderma vegetans. This is the first case of PV beginning from early infancy in the setting of primary immunodeficiency and in an unusual location. PMID:26170528

  5. Pyoderma Vegetans: A Case Report in a Child Suspected to Primary Immunodeficiency and Review of the Literature.

    PubMed

    Mansouri, Mahboubeh; Rakhshan, Azadeh; Shahidi-Dadras, Mohammad; Karimi, Abdollah; Alavi, Samin

    2015-07-01

    Pyoderma vegetans (PV) is a rare inflammatory disorder characterized by vegetating pustules and plaques affecting the skin and mucosal membranes. It is believed that this entity is mostly associated with inflammatory bowel disease (IBD), chronic malnutrition, human immunodeficiency virus (HIV), malignancies, and other immunocompromised states. Pyoderma vegetans occurs more commonly in young and middle-aged adults. There is no sex predilection for this entity. The lesions could heal spontaneously, but usually recur and become chronic. Our patient was an 11-year-old girl suspected to have primary combined immunodeficiency complicated by chronic recurrent vegetating pustular lesions on the face and postauricular area since one year of age. The histological features of the lesions were consistent with pyoderma vegetans. This is the first case of PV beginning from early infancy in the setting of primary immunodeficiency and in an unusual location. PMID:26170528

  6. Subcutaneous immunoglobulin therapy: a new option for patients with primary immunodeficiency diseases

    PubMed Central

    Kobrynski, Lisa

    2012-01-01

    Since the 1950s, replacement of immunoglobulin G using human immunoglobulin has been the standard treatment for primary immunodeficiency diseases with defects in antibody production. These patients suffer from recurrent and severe infections, which cause lung damage and shorten their life span. Immunoglobulins given intravenously (IVIG) every 3–4 weeks are effective in preventing serious bacterial infections and improving the quality of life for treated patients. Administration of immunoglobulin subcutaneously (SCIG) is equally effective in preventing infections and has a lower incidence of serious adverse effects compared to IVIG. The tolerability and acceptability of SCIG has been demonstrated in numerous studies showing improvements in quality of life and a preference for subcutaneous immunoglobulin therapy in patients with antibody deficiencies. PMID:22956859

  7. Kiovig for primary immunodeficiency: reduced infusion and decreased costs per infusion.

    PubMed

    Connolly, Mark; Simoens, Steven

    2011-09-01

    Kiovig is a ready-to-use 10% liquid immunoglobulin preparation that is medically indicated for the treatment of primary immunodeficiency. This study aims to conduct an economic evaluation which compares the intravenous immunoglobulin (IVIg) preparations Kiovig, Multigam, and Sandoglobulin from the Belgian societal perspective. As three prospective studies have observed no difference in outcomes, a cost-minimization analysis is considered appropriate to evaluate differences in treatment costs that can arise from IVIgs. A decision-analytic model simulated treatment costs attributed to one infusion. Resource use data were derived from a Dutch costing study. Cost items included immunoglobulin costs, pharmacy administration and nursing costs, mini-forfait for hospital infusion, costs of adverse events, and lost productivity with 2009 as base year. Cost data were identified from published sources and Belgian hospital administrators. A probabilistic sensitivity analysis explored the impact of parameter uncertainty on cost results. Costs per infusion cycle in adult primary immunodeficiency patients were €1,046 (95% confidence interval: €1,006-1,093) with Kiovig; €1,102 (€1,064-1,147) with Multigam; and €1,147 (€1,108-1,193) with Sandoglobulin. The average cost savings per infusion with Kiovig as compared to Multigam and Sandoglobulin amounted to €56 and €101 per infusion. In conclusion, treatment costs with Kiovig were shown to be lower as compared to other IVIgs in Belgium. Reduced costs per infusion were attributed to lower costs associated with treating adverse events and the opportunity cost of nursing time and time off work for working adults. PMID:21570491

  8. Improving cellular therapy for primary immune deficiency diseases: Recognition, diagnosis, and management

    PubMed Central

    Griffith, Linda M.; Cowan, Morton J.; Notarangelo, Luigi D.; Puck, Jennifer M.; Buckley, Rebecca H.; Candotti, Fabio; Conley, Mary Ellen; Fleisher, Thomas A.; Gaspar, H. Bobby; Kohn, Donald B.; Ochs, Hans D.; O'Reilly, Richard J.; Rizzo, J. Douglas; Roifman, Chaim M.; Small, Trudy N.; Shearer, William T.

    2010-01-01

    More than 20 North American academic centers account for the majority of hematopoietic stem cell transplantation (HCT) procedures for primary immunodeficiency diseases (PIDs), with smaller numbers performed at additional sites. Given the importance of a timely diagnosis of these rare diseases and the diversity of practice sites, there is a need for guidance as to best practices in management of patients with PIDs before, during, and in follow-up for definitive treatment. In this conference report of immune deficiency experts and HCT physicians who care for patients with PIDs, we present expert guidance for (1) PID diagnoses that are indications for HCT, including severe combined immunodeficiency disease (SCID), combined immunodeficiency disease, and other non-SCID diseases; (2) the critical importance of a high degree of suspicion of the primary care physician and timeliness of diagnosis for PIDs; (3) the need for rapid referral to an immune deficiency expert, center with experience in HCT, or both for patients with PIDs; (4) medical management of a child with suspicion of SCID/combined immunodeficiency disease while confirming the diagnosis, including infectious disease management and workup; (5) the posttransplantation follow-up visit schedule; (6) antimicrobial prophylaxis after transplantation, including gamma globulin administration; and (7) important indications for return to the transplantation center after discharge. Finally, we discuss the role of high-quality databases in treatment of PIDs and HCTas an element of the infrastructure that will be needed for productive multicenter clinical trials in these rare diseases. PMID:20004776

  9. Characterization of Primary Isolate-Like Variants of Simian-Human Immunodeficiency Virus

    PubMed Central

    Crawford, John M.; Earl, Patricia L.; Moss, Bernard; Reimann, Keith A.; Wyand, Michael S.; Manson, Kelledy H.; Bilska, Miroslawa; Zhou, Jin Tao; Pauza, C. David; Parren, Paul W. H. I.; Burton, Dennis R.; Sodroski, Joseph G.; Letvin, Norman L.; Montefiori, David C.

    1999-01-01

    Several different strains of simian-human immunodeficiency virus (SHIV) that contain the envelope glycoproteins of either T-cell-line-adapted (TCLA) strains or primary isolates of human immunodeficiency virus type 1 (HIV-1) are now available. One of the advantages of these chimeric viruses is their application to studies of HIV-1-specific neutralizing antibodies in preclinical AIDS vaccine studies in nonhuman primates. In this regard, an important consideration is the spectrum of antigenic properties exhibited by the different envelope glycoproteins used for SHIV construction. The antigenic properties of six SHIV variants were characterized here in neutralization assays with recombinant soluble CD4 (rsCD4), monoclonal antibodies, and serum samples from SHIV-infected macaques and HIV-1-infected individuals. Neutralization of SHIV variants HXBc2, KU2, 89.6, and 89.6P by autologous and heterologous sera from SHIV-infected macaques was restricted to an extent that these viruses may be considered heterologous to one another in their major neutralization determinants. Little or no variation was seen in the neutralization determinants on SHIV variants 89.6P, 89.6PD, and SHIV-KB9. Neutralization of SHIV HXBc2 by sera from HXBc2-infected macaques could be blocked with autologous V3-loop peptide; this was less true in the case of SHIV 89.6 and sera from SHIV 89.6-infected macaques. The poorly immunogenic but highly conserved epitope for monoclonal antibody IgG1b12 was a target for neutralization on SHIV variants HXBc2, KU2, and 89.6 but not on 89.6P and KB9. The 2G12 epitope was a target for neutralization on all five SHIV variants. SHIV variants KU2, 89.6, 89.6P, 89.6PD, and KB9 exhibited antigenic properties characteristic of primary isolates by being relatively insensitive to neutralization in peripheral blood mononuclear cells with serum samples from HIV-1-infected individuals and 12-fold to 38-fold less sensitive to inhibition with recombinant soluble CD4 than TCLA

  10. Recurrent Infections May Signal Immunodeficiencies

    MedlinePlus

    ... Search AAAAI Breadcrumb navigation Home ▸ Conditions & Treatments ▸ Library ▸ Primary Immunodeficiency Disease Library ▸ Recurrent Infections May Signal Immunodeficiencies Share | Recurrent Infections May Signal Immunodeficiencies This article has been reviewed by Thanai Pongdee, MD, FAAAAI ...

  11. Subcutaneous immunoglobulin replacement therapy in the treatment of patients with primary immunodeficiency disease

    PubMed Central

    Skoda-Smith, Suzanne; Torgerson, Troy R; Ochs, Hans D

    2010-01-01

    Antibody deficiency is the most frequently encountered primary immunodeficiency disease (PIDD) and patients who lack the ability to make functional immunoglobulin require life-long replacement therapy to prevent serious bacterial infections. Human serum immunoglobulin manufactured from pools of donated plasma can be administered intramuscularly, intravenously or subcutaneously. With the advent of well-tolerated preparations of intravenous immunoglobulin (IVIg) in the 1980s, the suboptimal painful intramuscular route of administration is no longer used. However, some patients continued to experience unacceptable adverse reactions to the intravenous preparations, and for others, vascular access remained problematic. Subcutaneously administered immunoglobulin (SCIg) provided an alternative delivery method to patients experiencing difficulties with IVIg. By 2006, immunoglobulin preparations designed exclusively for subcutaneous administration became available. They are therapeutically equivalent to intravenous preparations and offer patients the additional flexibility for the self-administration of their product at home. SCIg as replacement therapy for patients with primary antibody deficiencies is a safe and efficacious method to prevent serious bacterial infections, while maximizing patient satisfaction and improving quality of life. PMID:20169031

  12. Replication of human immunodeficiency virus type 1 in primary dendritic cell cultures.

    PubMed Central

    Langhoff, E; Terwilliger, E F; Bos, H J; Kalland, K H; Poznansky, M C; Bacon, O M; Haseltine, W A

    1991-01-01

    The ability of the human immunodeficiency virus type 1 (HIV-1) to replicate in primary blood dendritic cells was investigated. Dendritic cells compose less than 1% of the circulating leukocytes and are nondividing cells. Highly purified preparations of dendritic cells were obtained using recent advances in cell fractionation. The results of these experiments show that dendritic cells, in contrast to monocytes and T cells, support the active replication of all strains of HIV-1 tested, including T-cell tropic and monocyte/macrophage tropic isolates. The dendritic cell cultures supported much more virus production than did cultures of primary unseparated T cells, CD4+ T cells, and adherent as well as nonadherent monocytes. Replication of HIV-1 in dendritic cells produces no noticeable cytopathic effect nor does it decrease total cell number. The ability of the nonreplicating dendritic cells to support high levels of replication of HIV-1 suggests that this antigen-presenting cell population, which is also capable of supporting clonal T-cell growth, may play a central role in HIV pathogenesis, serving as a source of continued infection of CD4+ T cells and as a reservoir of virus infection. Images PMID:1910172

  13. Variable course of primary simian immunodeficiency virus infection in lymph nodes: relation to disease progression.

    PubMed Central

    Chakrabarti, L; Cumont, M C; Montagnier, L; Hurtrel, B

    1994-01-01

    To investigate the dynamics of spread of simian immunodeficiency virus (SIV) in the lymphoid organs, we sequentially analyzed the viral burden in lymph nodes (LN) of eight rhesus macaques inoculated intravenously with a high or low dose of the pathogenic SIVmac 251 isolate. For each animal, four axillary or inguinal LN were collected during the first weeks of infection and a fifth LN was taken 6 or 8 months later to estimate disease progression. Measurement of SIV RNA by in situ hybridization showed that all of the macaques studied had a phase of acute viral replication in LN between 7 and 14 days postinoculation which paralleled that observed in the blood. In a second phase, productive infection was controlled and viral particles were trapped in the germinal centers that developed in LN. While the peaks of productive infection were similar for the eight animals, marked differences in the numbers of productively infected cells that persisted in LN after primary infection were seen. Differences were less pronounced in the blood, where productive infection was efficiently controlled in all cases. The persistence of productively infected cells in LN after primary infection was found to be associated with more rapid disease progression, as measured by the decrease of the T4/T8 ratio and the occurrence of clinical signs. However, the persistence of a significant level of viral particles in germinal centers was observed even in animals that remained healthy over a 1- to 2-year observation period. This study indicates that the course of primary SIV infection in LN is variable, and it suggests that the initial capacity of the host to control productive infection in LN may determine the rate of disease progression. Images PMID:7916061

  14. Kinetics of cytokine expression during primary human immunodeficiency virus type 1 infection.

    PubMed Central

    Graziosi, C; Gantt, K R; Vaccarezza, M; Demarest, J F; Daucher, M; Saag, M S; Shaw, G M; Quinn, T C; Cohen, O J; Welbon, C C; Pantaleo, G; Fauci, A S

    1996-01-01

    In the present study, we have determined the kinetics of constitutive expression of a panel of cytokines [interleukin (IL) 2, IL-4, IL-6, IL-10, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha)] in sequential peripheral blood mononuclear cell samples from nine individuals with primary human immunodeficiency virus infection. Expression of IL-2 and IL-4 was barely detected in peripheral blood mononuclear cells. However, substantial levels of IL-2 expression were found in mononuclear cells isolated from lymph node. Expression of IL-6 was detected in only three of nine patients, and IL-6 expression was observed when transition from the acute to the chronic phase had already occurred. Expression of IL-10 and TNF-alpha was consistently observed in all patients tested, and levels of both cytokines were either stable or progressively increased over time. Similar to IL-10 and TNF-alpha, IFN-gamma expression was detected in all patients; however, in five of nine patients, IFN-gamma expression peaked very early during primary infection. The early peak in IFN-gamma expression coincided with oligoclonal expansions of CD8+ T cells in five of six patients, and CD8+ T cells mostly accounted for the expression of this cytokine. These results indicate that high levels of expression of proinflammatory cytokines are associated with primary infection and that the cytokine response during this phase of infection is strongly influenced by oligoclonal expansions of CD8+ T cells. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8633076

  15. IL-21-producer CD4+ T cell kinetics during primary simian immunodeficiency virus infection.

    PubMed

    Shi, Shoi; Seki, Sayuri; Matano, Tetsuro; Yamamoto, Hiroyuki

    2013-01-01

    IL-21 signaling is important for T cell and B cell-mediated clearance of chronic viral infections. While non-cognate follicular helper CD4+ T cells (TFH) are indicated to be pivotal in providing IL-21-mediated help to activated B cells within germinal centers, how this signaling may be disrupted in early AIDS virus infection is not clear. In this study, we assessed the lineage and kinetics of peripheral blood IL-21-producing CD4+ T cells in primary simian immunodeficiency virus (SIV) infection of rhesus macaques. After SIV challenge, antigen-nonspecific IL-21 production was observed in Th1, Th2 and Th17 cells with Th1 dominance. While IL-21+ Th2 and IL-21+ Th17 showed variable kinetics, an increase in total IL-21+ CD4+ T cells and IL-21+ Th1 from week 3 to week 8 was observed, preceding plasma SIV-specific IgG development from week 5 to week 12. SIV Gag-specific IL-21+ CD4+ T cells detectable at week 2 were decreased in frequencies at week 5. Results imply that kinetics of IL-21+ CD4+ T cells comprised of multiple lineages, potentially targeted by SIV with a bias of existing frequencies during their precursor stage, associate with availability of cooperative B-cell help provided through a proportionate precursor pool developing into TFH and subsequent anti-SIV antibody responses. PMID:23791954

  16. Subcutaneous immunoglobulins: product characteristics and their role in primary immunodeficiency disease.

    PubMed

    Melamed, Isaac; Testori, Alessandro; Spirer, Zvi

    2012-12-01

    Research on the role of subcutaneous immunoglobulin in primary immunodeficiency disease (PIDD) is ongoing. We analyzed pivotal studies for four subcutaneous immunoglobulin products: IGSC 10% (Gammagard(®) Liquid), IGIV-C 10% (Gamunex(®)-C), IGSC 16% (Vivaglobin(®)) and IGSC 20% (Hizentra(®)). To identify similarities and differences between products, we examined infusion parameters, adverse event profiles and improvements in tolerability over time. Maximum volume infused was 30 mL/site for IGSC 10%, 34 mL/site for IGIV-C 10%, 15 mL/site for IGSC 16% and 25 mL/site for IGSC 20%. Maximum number of simultaneous infusion sites was 10 for IGSC 10%, 8 for IGIV-C 10%, 6 for IGSC 16% and 4 for IGSC 20%. Local adverse reaction rate per infusion was 0.02 for IGSC 10%, 0.59 for IGIV-C, 0.49 for IGSC 16% and 0.58 for IGSC 20%. IGSC products have similar efficacy profiles; however, their tolerability profiles vary. Reasons for these differences are unknown and warrant further research. PMID:23215767

  17. Genetic and Functional Diversity of Human Immunodeficiency Virus Type 1 Subtype B Nef Primary Isolates

    PubMed Central

    Foster, John L.; Molina, Rene P.; Luo, Tianci; Arora, Vivek K.; Huang, Yaoxing; Ho, David D.; Garcia, J. Victor

    2001-01-01

    We have characterized the functional integrity of seven primary Nef isolates: five from a long-term nonprogressing human immunodeficiency virus (HIV)-infected individual and one each from two patients with AIDS. One of the seven Nefs was defective for CD4 downregulation, two others were defective for PAK-2 activation, and one Nef was defective for PAK-2 activation and major histocompatibility complex (MHC) class I downregulation. Five of the Nefs were tested and found to be functional for the enhancement of virus particle infectivity. The structural basis for each of the functional defects has been analyzed by constructing a consensus nef, followed by mutational analysis of the variant amino acid residues. Mutations A29V and F193I were deleterious to CD4 downregulation and PAK-2 activation, respectively, while S189R rendered Nef defective for both MHC class I downregulation and PAK-2 activation. A search of the literature identified HIVs from five patients with Nefs predominantly mutated at F193 and from one patient with Nefs predominantly mutated at A29. A29 is highly conserved in all HIV subtypes except for subtype E. F193 is conserved in subtype B (and possibly in the closely related subtype D), but none of the other HIV group M subtypes. Our results suggest that functional distinctions may exist between HIV subtypes. PMID:11160665

  18. Hematopoietic stem cell transplantation for children with primary immunodeficiency diseases: single center experience in Jordan.

    PubMed

    Amayiri, Nisreen; Al-Zaben, Abdulhadi; Ghatasheh, Lubna; Frangoul, Haydar; Hussein, Ayad Ahmed

    2013-06-01

    HSCT can be curative for many PID. Little is known about the outcome of HSCT for patients with PID in the developing countries. We retrospectively reviewed all children with PID who received HSCT at KHCC in Jordan between August 2003 and October 2011. Twenty-eight patients were identified. The median age was 16 months (3 months-17 yr). Patients' diagnoses were SCID (n = 16), CHS (n = 3), HLH (n = 3), WAS (n = 2), Griscelli syndrome (n = 1), ALPS (n = 1), Omenn's syndrome (n = 1), and DiGeorge syndrome (n = 1). Seventeen patients received HLA-matched related HSCT, eight received maternal un-manipulated haploidentical HSCT, and three received unrelated cord blood transplantation. Nine patients (32%) developed BCGosis secondary to reactivation of pretransplant vaccination. Three died while still receiving anti-tuberculosis drugs, one still on treatment, and all others have recovered. Six patients had graft failure; four of them received no conditioning regimens. At a median follow up of 32 months (range 1-67), 21 patients are alive, with overall survival of 72%. We conclude that HSCT for PID patients can be performed with a good outcome in developing countries; however, delayed diagnosis or referral and BCG reactivation are unique challenges. PMID:23692601

  19. Pelvic Inflammatory Disease (PID)

    MedlinePlus

    ... herpes, syphilis, and infection with human immunodeficiency virus (HIV, the cause of acquired immunodeficiency syndrome [AIDS]). Ultrasonography: A test in which sound waves are used to examine internal structures. During pregnancy, it can be used to examine ...

  20. Disseminated bronchiectasis in an adult with common variable immunodeficiency.

    PubMed

    Zea-Vera, Andrés Felipe; Agudelo-Rojas, Olga Lucia

    2015-01-01

    Primary immunodeficiencies (PID) are traditionally considered childhood diseases; however, adults account for 35% of all patients with PID. Antibody deficiencies, especially Common Variable Immunodeficiency (CVID), which have their peak incidence in adulthood, require a high suspicion index. Even though the estimated frequency of CVID is not high (1:25,000), high rates of under diagnosis and under reporting are very likely. The delay in diagnosis increases the morbidity and mortality; therefore, adult physicians should be able to suspect, identify and initiate management of individuals with PID. Here we report the case of a 37 year-old man presenting to the emergency room with dyspnea, fever and cough; he developed respiratory failure requiring mechanical ventilation. He complained of recurring pneumonia associated with widespread bronchiectasis since he was 18 years old. Serum immunoglobulins quantification showed severe hypogammaglobulinemia (total IgG <140 mg/dL; total IgA, 2.9 mg/dL; and total IgM <5 mg/dL). Treatment with Human Intravenous Immunoglobulin (IVIG) 10% was started, and with antibiotic treatment for severe pneumonia (during 14 days) was also prescribed. His clinical evolution has been favorable after one year follow-up. Common Variable Immunodeficiency (CVID) diagnosis was made. PMID:26019385

  1. Mucosal-Associated Invariant T (MAIT) Cells Are Impaired in Th17 Associated Primary and Secondary Immunodeficiencies.

    PubMed

    Gao, Yifang; Rae, William; Ramakrishnan, Keseva Ananth; Barcenas-Morales, Gabriela; Döffinger, Rainer; Eren, Efrem; Faust, Saul N; Ottensmeier, Christian H; Williams, Anthony P

    2016-01-01

    The recently described Mucosal Associated Invariant T (MAIT) cells mediate specific recognition of bacterial and fungal vitamin B2 metabolites. As innate T cells, they possess broad effector responses, including IFN- including Iproduction, that are comparable to conventional T cell responses. Immunodeficiencies associated with systemic Th17 deficiency may also be compounded by defects in MAIT immunity. We evaluated Th17 immunity in this innate T cell compartment in primary (AD-HIES) and secondary immunodeficiency (thymoma) patients with conventional Th17 deficiency and susceptibility to fungal and bacterial disease. Our results suggest that MAIT cells are both reduced and functional deficient in STAT3 deficiency and thymoma patients with IL-12/23 autoantibodies. In contrast, thymoma patients without autoantibodies preserved the normal number and functional MAIT cells. PMID:27167980

  2. Mucosal-Associated Invariant T (MAIT) Cells Are Impaired in Th17 Associated Primary and Secondary Immunodeficiencies

    PubMed Central

    Gao, Yifang; Rae, William; Ramakrishnan, Keseva Ananth; Barcenas-Morales, Gabriela; Döffinger, Rainer; Eren, Efrem; Faust, Saul N.; Ottensmeier, Christian H.; Williams, Anthony P.

    2016-01-01

    The recently described Mucosal Associated Invariant T (MAIT) cells mediate specific recognition of bacterial and fungal vitamin B2 metabolites. As innate T cells, they possess broad effector responses, including IFN- including Iproduction, that are comparable to conventional T cell responses. Immunodeficiencies associated with systemic Th17 deficiency may also be compounded by defects in MAIT immunity. We evaluated Th17 immunity in this innate T cell compartment in primary (AD-HIES) and secondary immunodeficiency (thymoma) patients with conventional Th17 deficiency and susceptibility to fungal and bacterial disease. Our results suggest that MAIT cells are both reduced and functional deficient in STAT3 deficiency and thymoma patients with IL-12/23 autoantibodies. In contrast, thymoma patients without autoantibodies preserved the normal number and functional MAIT cells. PMID:27167980

  3. TOXIRAE PRO PID

    EPA Science Inventory

    The ToxiRAE Pro PID measures total volatile organic compounds (VOCs) using a photoionization detector (PID). This sensor can be programmed to measure concentrations of a specified compound automatically and has a real time reading of VOC concentrations in parts per million (ppm) ...

  4. Efficacy and safety of home-based subcutaneous immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies.

    PubMed

    Borte, M; Bernatowska, E; Ochs, H D; Roifman, C M

    2011-06-01

    Subcutaneous immunoglobulin infusions are effective, safe and well tolerated in the treatment of primary immunodeficiencies, but only limited data on the treatment of children are available. We investigated the efficacy, safety and pharmacokinetics of home therapy with a 16% liquid human immunoglobulin G preparation (Vivaglobin®) when administered subcutaneously in children with primary immunodeficiencies. Data were analysed from 22 children (2-<12 years) who participated in two prospective, open-label studies (one in Europe/Brazil, one in North America). All children had previously received intravenous immunoglobulins. They started weekly subcutaneous immunoglobulin infusions with an approximately 3-month wash-in/wash-out period, followed by a 6-month (Europe/Brazil) or 12-month (North America) efficacy evaluation period. In Europe/Brazil, subcutaneous doses generally equalled the previous weekly equivalent intravenous doses. In North America, subcutaneous doses during the efficacy evaluation period were 126% (median) of the previous weekly equivalent intravenous doses. Efficacy end-points in both studies included the occurrence of serious bacterial infections and any infections, and serum immunoglobulin G trough levels. Median serum immunoglobulin G trough levels exceeded those during previous intravenous therapy by 13% (North America) and 16% (Europe/Brazil). During the efficacy evaluation period of both studies, none of the children had a serious bacterial infection; the mean overall infection rate/patient year was 4·7 in Europe/Brazil and 5·6 in North America, concurring with previous reports in adults. The adverse event profile was comparable to previous reports in adults. Both studies confirmed the efficacy and safety of subcutaneous immunoglobulin therapy with Vivaglobin in children with primary immunodeficiencies. PMID:21413943

  5. Efficacy and safety of home-based subcutaneous immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies

    PubMed Central

    Borte, M; Bernatowska, E; Ochs, H D; Roifman, C M

    2011-01-01

    Subcutaneous immunoglobulin infusions are effective, safe and well tolerated in the treatment of primary immunodeficiencies, but only limited data on the treatment of children are available. We investigated the efficacy, safety and pharmacokinetics of home therapy with a 16% liquid human immunoglobulin G preparation (Vivaglobin®) when administered subcutaneously in children with primary immunodeficiencies. Data were analysed from 22 children (2–<12 years) who participated in two prospective, open-label studies (one in Europe/Brazil, one in North America). All children had previously received intravenous immunoglobulins. They started weekly subcutaneous immunoglobulin infusions with an approximately 3-month wash-in/wash-out period, followed by a 6-month (Europe/Brazil) or 12-month (North America) efficacy evaluation period. In Europe/Brazil, subcutaneous doses generally equalled the previous weekly equivalent intravenous doses. In North America, subcutaneous doses during the efficacy evaluation period were 126% (median) of the previous weekly equivalent intravenous doses. Efficacy end-points in both studies included the occurrence of serious bacterial infections and any infections, and serum immunoglobulin G trough levels. Median serum immunoglobulin G trough levels exceeded those during previous intravenous therapy by 13% (North America) and 16% (Europe/Brazil). During the efficacy evaluation period of both studies, none of the children had a serious bacterial infection; the mean overall infection rate/patient year was 4·7 in Europe/Brazil and 5·6 in North America, concurring with previous reports in adults. The adverse event profile was comparable to previous reports in adults. Both studies confirmed the efficacy and safety of subcutaneous immunoglobulin therapy with Vivaglobin in children with primary immunodeficiencies. PMID:21413943

  6. Primary Neuritic Hansen's Disease presenting as Ulnar Nerve Abscess in a Human Immunodeficiency Virus Positive Patient.

    PubMed

    Karjigi, S; Herakal, K; Murthy, S C; Bathina, A; Kusuma, M R; Nikhil, K R Y

    2015-01-01

    Leprosy has been increasingly known to have an enigmatic relationship with human immunodeficiency virus infection. Co-infection may result in atypical manifestations of leprosy. A 45-year old human immunodeficiency virus-positive male; agricultural laborer presented with a swelling over right elbow, right hand deformity, generalized itching and recurrent vesicles overthe perinasal area. Clinical and investigational findings were consistent with mononeuritic type of Hansen's disease with right sided silent ulnar nerve abscess, partial claw hand. CD4+ count of the patientwas 430 cells/cmm. This patient also hadherpes simplex labialis, with HIV-associated pruritus. To the best of our knowledge such an atypical presentation has not been reported earlier. PMID:26999990

  7. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.

    PubMed Central

    Koup, R A; Safrit, J T; Cao, Y; Andrews, C A; McLeod, G; Borkowsky, W; Farthing, C; Ho, D D

    1994-01-01

    Virologic and immunologic studies were performed on five patients presenting with primary human immunodeficiency virus type 1 (HIV-1) infection. CD8+ cytotoxic T lymphocyte (CTL) precursors specific for cells expressing antigens of HIV-1 Gag, Pol, and Env were detected at or within 3 weeks of presentation in four of the five patients and were detected in all five patients by 3 to 6 months after presentation. The one patient with an absent initial CTL response had prolonged symptoms, persistent viremia, and low CD4+ T-cell count. Neutralizing antibody activity was absent at the time of presentation in all five patients. These findings suggest that cellular immunity is involved in the initial control of virus replication in primary HIV-1 infection and indicate a role for CTL in protective immunity to HIV-1 in vivo. PMID:8207839

  8. Primary immunodeficiency syndromes associated with defective DNA double-strand break repair.

    PubMed

    Gennery, A R

    2006-01-01

    Damaging DNA double-strand breaks (DNA-DSBs) following ionizing radiation (IR) exposure, potentially lead to cell death or carcinogenesis. Non-homologous end-joining (NHEJ) is the main repair pathway employed by vertebrate cells to repair such damage. Many repair pathway proteins have been identified. The creation of many diverse lymphocyte receptors to identify potential pathogens has evolved by breaking and randomly re-sorting the gene segments coding for antigen receptors. Subsequent DNA-DSB repair utilizes the NHEJ proteins. Individuals with defective repair pathways are increasingly recognized with radiosensitivity and immunodeficiency. Patients with defects in ataxia-telangiectasia mutated, nibrin, MRE11, Rad50, Artemis, DNA ligase IV and Cernunnos-XRCC4-like factor have been identified. Most exhibit immunodeficiency, with a spectrum of presentation and overlap between conditions. Conventional treatment with immunoglobulin replacement or haematopoietic stem cell transplantation (HSCT) can be effective. A greater understanding of the molecular defect will enable better, tailored therapies to improve survival. PMID:16971555

  9. LONG-TERM SURVIVAL AND LATE DEATHS AFTER HEMATOPOIETIC CELL TRANSPLANTATION FOR PRIMARY IMMUNODEFICIENCY DISEASES AND INBORN ERRORS OF METABOLISM

    PubMed Central

    Eapen, Mary; Ahn, Kwang Woo; Orchard, Paul J.; Cowan, Morton J.; Davies, Stella M.; Fasth, Anders; Hassebroek, Anna; Ayas, Mouhab; Bonfim, Carmem; O’Brien, Tracey A.; Gross, Thomas G.; Horwitz, Mitchell; Horwitz, Edwin; Kapoor, Neena; Kurtzberg, Joanne; Majhail, Navneet; Ringden, Olle; Szabolcs, Paul; Veys, Paul; Baker, K. Scott

    2012-01-01

    It is uncertain whether late mortality rates after hematopoietic cell transplantation for severe combined immunodeficiency (SCID), non-SCID primary immunodeficiency diseases (non-SCID PIDD) and inborn error of metabolism (IEM) return to rates observed in the general population, matched for age, sex and nationality. We studied patients with SCID (n=201), non-SCID PIDD (n=405) and IEM (n=348) who survived for at least two years after transplantation with normal T-cell function (SCID) or >95% donor chimerism (non-SCID PIDD and IEM). Importantly, mortality rates were significantly higher than for the general population for several years after transplantation. This decreases towards normal rates in patients with SCID and non-SCID PIDD beyond 6 years after transplantation but not for IEM. Active chronic graft-versus-host disease at 2-years was associated with higher risks of late mortality for all diseases (HR 1.87, p=0.05). Additionally, for non-SCID PIDD, late mortality was higher in recipients of T-cell depleted grafts (HR 4.16, p=0.007) and for IEM, after unrelated donor (HR 2.72, p=0.03) and mismatched related donor (HR 3.76, p=0.01) transplants. The higher mortality rates in these long-term survivors for many years after transplantation confirm the need for long-term surveillance. PMID:22430083

  10. Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: A working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology.

    PubMed

    Yong, Pierre L; Boyle, John; Ballow, Mark; Boyle, Marcia; Berger, Melvin; Bleesing, Jack; Bonilla, Franciso A; Chinen, Javier; Cunninghamm-Rundles, Charlotte; Fuleihan, Ramsay; Nelson, Lois; Wasserman, Richard L; Williams, Kathleen C; Orange, Jordan S

    2010-05-01

    There are an expanding number of primary immunodeficiency diseases (PIDDs), each associated with unique diagnostic and therapeutic complexities. Limited data, however, exist supporting specific therapeutic interventions. Thus, a survey of PIDD management was administered to allergists/immunologists in the United States to identify current perspectives and practices. Among 405 respondents, the majority of key management practices identified were consistent with existing data and guidelines, including the provision of immunoglobulin therapy, immunoglobulin dosing and selective avoidance of live viral vaccines. Practices for which there are little specific data or evidence-based guidance were also examined, including evaluation of IgG trough levels for patients receiving immunoglobulin, use of prophylactic antibiotics and recommendations for complementary/alternative medicine. Here, variability applied to PIDD patients was identified. Differences between practitioners clinically focused upon PIDD and general allergists/immunologists were also identified. Thus, a need for expanded clinical research in PIDD to optimize management and potentially improve outcomes was defined. PMID:19914873

  11. Pharmacokinetics of a new 10% intravenous immunoglobulin in patients receiving replacement therapy for primary immunodeficiency.

    PubMed

    Wasserman, Richard L; Church, Joseph A; Peter, Hans H; Sleasman, John W; Melamed, Isaac; Stein, Mark R; Bichler, Johann

    2009-06-28

    Intravenous immunoglobulin (IVIg) is used in treating immunodeficiencies and autoimmune or inflammatory disorders. As manufacturing processes and storage can alter IgG molecules, pharmacokinetic assessments are important for new preparations. Thus, we studied pharmacokinetics of IgPro10, a new 10% liquid IVIg product stabilised with l-proline, in patients with common variable immunodeficiency (CVID) and X-linked agammaglobulinaemia (XLA). Patients received IgPro10 for >or=4 months (median dose of 444mg/kg, at 3- or 4-week intervals). Median total IgG serum concentrations increased from 10.2g/l pre-infusion to 23.2g/l at infusion end. Serum IgG concentrations decreased in a biphasic manner; median terminal half-life was 36.6 days. Median half-lives were 33.2 for IgG(1), 36.3 for IgG(2), 25.9 for IgG(3) and 36.4 days for IgG(4). Specific antibody concentrations (anti-CMV, anti-Hemophilus influenzae type B, anti-tetanus toxoid and anti-Streptococcus pneumoniae) decreased with median half-lives of 22.3-30.5 days. IgPro10 pharmacokinetics were similar in patients with CVID and XLA, although patients with CVID showed higher levels of anti-tetanus and anti-S. pneumoniae antibodies than patients with XLA, suggesting residual specific antibody production. IgPro10 pharmacokinetics fulfilled expectations for and were similar to intact IgG products. Administration of IgPro10 at 3- or 4-week intervals achieved sufficient plasma concentrations of total IgG, IgG subclasses and antibodies specific to important pathogens. PMID:19491015

  12. Pelvic Inflammatory Disease (PID)

    MedlinePlus

    ... a serious condition, in women. 1 in 8 women with a history of PID experience difficulties getting pregnant. You can ... negative STD test results; • Using latex condoms the right way every time you have ... your medical history, physical exam, and other test results. You may ...

  13. Advances in neonatal screening for primary immune deficiencies

    PubMed Central

    JIANG, TINGTING; LI, ZHENGUANG; ZHANG, QIULI

    2016-01-01

    The congenital disorders of immune competence are known as primary immunodeficiencies (PID) and are mainly characterized by a pathological susceptibility to infection. These infections are mostly of time repetitive and drug resistant in nature. The number of infected infants has reached over 200 and is on the increase. Additionally, clinical severity of the disease has been confirmed to be extensive. The increasing number of these severe PIDs is due to the lack of specific as well as efficient management avenues. New assays and concepts for newborn screening of severe primary immune deficiencies are being explored and the present review focused on these new upcoming strategies for improved screening of neonates. PMID:27168770

  14. Determinants of human immunodeficiency virus type 1 escape from the primary CD8+ cytotoxic T lymphocyte response.

    PubMed

    Jones, Nicola A; Wei, Xiping; Flower, Darren R; Wong, Mailee; Michor, Franziska; Saag, Michael S; Hahn, Beatrice H; Nowak, Martin A; Shaw, George M; Borrow, Persephone

    2004-11-15

    CD8+ cytotoxic T lymphocytes (CTLs) play an important role in containment of virus replication in primary human immunodeficiency virus (HIV) infection. HIV's ability to mutate to escape from CTL pressure is increasingly recognized; but comprehensive studies of escape from the CD8 T cell response in primary HIV infection are currently lacking. Here, we have fully characterized the primary CTL response to autologous virus Env, Gag, and Tat proteins in three patients, and investigated the extent, kinetics, and mechanisms of viral escape from epitope-specific components of the response. In all three individuals, we observed variation beginning within weeks of infection at epitope-containing sites in the viral quasispecies, which conferred escape by mechanisms including altered peptide presentation/recognition and altered antigen processing. The number of epitope-containing regions exhibiting evidence of early CTL escape ranged from 1 out of 21 in a subject who controlled viral replication effectively to 5 out of 7 in a subject who did not. Evaluation of the extent and kinetics of HIV-1 escape from >40 different epitope-specific CD8 T cell responses enabled analysis of factors determining escape and suggested that escape is restricted by costs to intrinsic viral fitness and by broad, codominant distribution of CTL-mediated pressure on viral replication. PMID:15545352

  15. CCR6 Functions as a New Coreceptor for Limited Primary Human and Simian Immunodeficiency Viruses

    PubMed Central

    Islam, Salequl; Shimizu, Nobuaki; Hoque, Sheikh Ariful; Jinno-Oue, Atsushi; Tanaka, Atsushi; Hoshino, Hiroo

    2013-01-01

    More than 12 chemokine receptors (CKRs) have been identified as coreceptors for the entry of human immunodeficiency virus type 1 (HIV-1), type 2 (HIV-2), and simian immunodeficiency viruses (SIVs) into target cells. The expression of CC chemokine receptor 6 (CCR6) on Th17 cells and regulatory T cells make the host cells vulnerable to HIV/SIV infection preferentially. However, only limited information is available concerning the specific role of CCR6 in HIV/SIV infection. We examined CCR6 as a coreceptor candidate in this study using NP-2 cell line-based in-vitro studies. Normally, CD4-transduced cell line, NP-2/CD4, is strictly resistant to all HIV/SIV infection. When CCR6 was transduced there, the resultant NP-2/CD4/CCR6 cells became susceptible to HIV-1HAN2, HIV-2MIR and SIVsmE660, indicating coreceptor roles of CCR6. Viral antigens in infected cells were detected by IFA and confirmed by detection of proviral DNA. Infection-induced syncytia in NP-2/CD4/CCR6 cells were detected by Giemsa staining. Amount of virus release through CCR6 has been detected by RT assay in spent culture medium. Sequence analysis of proviral DNA showed two common amino acid substitutions in the C2 envelope region of HIV-2MIR clones propagated through NP-2/CD4/CCR6 cells. Conversely, CCR6-origin SIVsmE660 clones resulted two amino acid changes in the V1 region and one change in the C2 region. The substitutions in the C2 region for HIV-2MIR and the V1 region of SIVsmE660 may confer selection advantage for CCR6-use. Together, the results describe CCR6 as an independent coreceptor for HIV and SIV in strain-specific manner. The alteration of CCR6 uses by viruses may influence the susceptibility of CD4+ CCR6+ T-cells and dendritic cell subsets in vivo and therefore, is important for viral pathogenesis in establishing latent infections, trafficking, and transmission. However, clinical relevance of CCR6 as coreceptor in HIV/SIV infections should be investigated further. PMID:24009735

  16. Primary Radiation Therapy for Head-and-Neck Cancer in the Setting of Human Immunodeficiency Virus

    SciTech Connect

    Klein, Emily A.; Guiou, Michael; Farwell, D. Gregory; Luu, Quang; Lau, Derick H.; Stuart, Kerri; Vaughan, Andrew; Vijayakumar, Srinivasan; Chen, Allen M.

    2011-01-01

    Purpose: To analyze outcomes after radiation therapy for head-and-neck cancer among a cohort of patients with human immunodeficiency virus (HIV). Methods and Materials: The medical records of 12 patients with serologic evidence of HIV who subsequently underwent radiation therapy to a median dose of 68 Gy (range, 64-72 Gy) for newly diagnosed squamous cell carcinoma of the head and neck were reviewed. Six patients (50%) received concurrent chemotherapy. Intensity-modulated radiotherapy was used in 6 cases (50%). All patients had a Karnofsky performance status of 80 or 90. Nine patients (75%) were receiving antiretroviral therapies at the time of treatment, and the median CD4 count was 460 (range, 266-800). Toxicity was graded according to the Radiation Therapy Oncology Group / European Organization for the Treatment of Cancer toxicity criteria. Results: The 3-year estimates of overall survival and local-regional control were 78% and 92%, respectively. Acute Grade 3+ toxicity occurred in 7 patients (58%), the most common being confluent mucositis (5 patients) and moist skin desquamation (4 patients). Two patients experienced greater than 10% weight loss, and none experienced more than 15% weight loss from baseline. Five patients (42%) experienced treatment breaks in excess of 10 cumulative days, although none required hospitalization. There were no treatment-related fatalities. Conclusions: Radiation therapy for head-and-neck cancer seems to be relatively well tolerated among appropriately selected patients with HIV. The observed rates of toxicity were comparable to historical controls without HIV.

  17. Human Immunodeficiency Virus and Depression in Primary Care: A Clinical Review

    PubMed Central

    Colibazzi, Tiziano; Hsu, Teresa T.; Gilmer, William S.

    2006-01-01

    Background: Human immunodeficiency virus (HIV)–infected individuals are at increased risk of developing depression. Depressive syndromes in these patients pose a challenge both diagnostically and therapeutically. These syndromes reflect both the presence of preexisting mood disorders and the development of depressive syndromes subsequent to HIV infection. Data Sources: A search of the literature to 2005 was performed using the PubMed and Ovid search engines. English- and Portuguese-language articles were identified using the following keywords: HIV or AIDS and depression, mental illness, suicide, fatigue, psychiatry, and drug interactions. Additional references were identified through bibliography reviews of relevant articles. Data Synthesis: The clinical presentation and differential diagnosis of depressive symptoms in HIV illness and the role of HIV in the development of these conditions are reviewed. Management issues including suicide assessment and treatment options are then discussed, and potentially important pharmacokinetic interactions are reviewed. Conclusions: Individuals with HIV show higher rates of depression. This phenomenon may be due to a preexisting psychiatric disorder or to the HIV infection. Untreated depression symptoms may lead to non-compliance with drug regimens or increased high-risk behaviors. Given the adverse sequelae of untreated depressions in HIV illness, identification and management of depression are integral components of comprehensive HIV care. PMID:16964315

  18. Dynamic PID loop control

    SciTech Connect

    Pei, L.; Klebaner, A.; Theilacker, J.; Soyars, W.; Martinez, A.; Bossert, R.; DeGraff, B.; Darve, C.; /Fermilab

    2011-06-01

    The Horizontal Test Stand (HTS) SRF Cavity and Cryomodule 1 (CM1) of eight 9-cell, 1.3GHz SRF cavities are operating at Fermilab. For the cryogenic control system, how to hold liquid level constant in the cryostat by regulation of its Joule-Thompson JT-valve is very important after cryostat cool down to 2.0 K. The 72-cell cryostat liquid level response generally takes a long time delay after regulating its JT-valve; therefore, typical PID control loop should result in some cryostat parameter oscillations. This paper presents a type of PID parameter self-optimal and Time-Delay control method used to reduce cryogenic system parameters oscillation.

  19. Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

    PubMed

    Chen, Huanhuan Joyce; Sun, Jian; Huang, Zhiliang; Hou, Harry; Arcilla, Myra; Rakhilin, Nikolai; Joe, Daniel J; Choi, Jiahn; Gadamsetty, Poornima; Milsom, Jeff; Nandakumar, Govind; Longman, Randy; Zhou, Xi Kathy; Edwards, Robert; Chen, Jonlin; Chen, Kai Yuan; Bu, Pengcheng; Wang, Lihua; Xu, Yitian; Munroe, Robert; Abratte, Christian; Miller, Andrew D; Gümüş, Zeynep H; Shuler, Michael; Nishimura, Nozomi; Edelmann, Winfried; Shen, Xiling; Lipkin, Steven M

    2015-06-01

    Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening. PMID:26006007

  20. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency.

    PubMed

    Maffucci, Patrick; Filion, Charles A; Boisson, Bertrand; Itan, Yuval; Shang, Lei; Casanova, Jean-Laurent; Cunningham-Rundles, Charlotte

    2016-01-01

    Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes. PMID:27379089

  1. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency

    PubMed Central

    Maffucci, Patrick; Filion, Charles A.; Boisson, Bertrand; Itan, Yuval; Shang, Lei; Casanova, Jean-Laurent; Cunningham-Rundles, Charlotte

    2016-01-01

    Whole exome sequencing (WES) has proven an effective tool for the discovery of genetic defects in patients with primary immunodeficiencies (PIDs). However, success in dissecting the genetic etiology of common variable immunodeficiency (CVID) has been limited. We outline a practical framework for using WES to identify causative genetic defects in these subjects. WES was performed on 50 subjects diagnosed with CVID who had at least one of the following criteria: early onset, autoimmune/inflammatory manifestations, low B lymphocytes, and/or familial history of hypogammaglobulinemia. Following alignment and variant calling, exomes were screened for mutations in 269 PID-causing genes. Variants were filtered based on the mode of inheritance and reported frequency in the general population. Each variant was assessed by study of familial segregation and computational predictions of deleteriousness. Out of 433 variations in PID-associated genes, we identified 17 probable disease-causing mutations in 15 patients (30%). These variations were rare or private and included monoallelic mutations in NFKB1, STAT3, CTLA4, PIK3CD, and IKZF1, and biallelic mutations in LRBA and STXBP2. Forty-two other damaging variants were found but were not considered likely disease-causing based on the mode of inheritance and/or patient phenotype. WES combined with analysis of PID-associated genes is a cost-effective approach to identify disease-causing mutations in CVID patients with severe phenotypes and was successful in 30% of our cohort. As targeted therapeutics are becoming the mainstay of treatment for non-infectious manifestations in CVID, this approach will improve management of patients with more severe phenotypes. PMID:27379089

  2. An env gene derived from a primary human immunodeficiency virus type 1 isolate confers high in vivo replicative capacity to a chimeric simian/human immunodeficiency virus in rhesus monkeys.

    PubMed Central

    Reimann, K A; Li, J T; Voss, G; Lekutis, C; Tenner-Racz, K; Racz, P; Lin, W; Montefiori, D C; Lee-Parritz, D E; Lu, Y; Collman, R G; Sodroski, J; Letvin, N L

    1996-01-01

    To explore the roles played by specific human immunodeficiency virus type 1 (HIV-1) genes in determining the in vivo replicative capacity of AIDS viruses, we have examined the replication kinetics and virus-specific immune responses in rhesus monkeys following infection with two chimeric simian/human immunodeficiency viruses (SHIVs). These viruses were composed of simian immunodeficiency virus SIVmac239 expressing HIV-1 env and the associated auxiliary HIV-1 genes tat, vpu, and rep. Virus replication was assessed during primary infection of rhesus monkeys by measuring plasma SIVmac p27 levels and by quantifying virus replication in lymph nodes using in situ hybridization. SHIV-HXBc2, which expresses the HIV-1 env of a T-cell-tropic, laboratory-adapted strain of HIV-1 (HXBc2), replicated well in rhesus monkey peripheral blood leukocytes (PBL) in vitro but replicated only to low levels when inoculated in rhesus monkeys. In contrast, SHIV-89.6 was constructed with the HIV-1 env gene of a T-cell- and macrophage-tropic clone of a patient isolate of HIV-1 (89.6). This virus replicated to a lower level in monkey PBL in vitro but replicated to a higher degree in monkeys during primary infection. Moreover, monkeys infected with SHIV-89.6 developed an inversion in the PBL CD4/CD8 ratio coincident with the clearance of primary viremia. The differences in the in vivo consequences of infection by these two SHIVs could not be explained by differences in the immune responses elicited by these viruses, since infected animals had comparable type-specific neutralizing antibody titers, proliferative responses to recombinant HIV-1 gp120, and virus-specific cytolytic effector T-cell responses. With the demonstration that a chimeric SHIV can replicate to high levels during primary infection in rhesus monkeys, this model can now be used to define genetic determinants of HIV-1 pathogenicity. PMID:8627800

  3. Predictors of Non-Uptake of Human Immunodeficiency Virus Testing by Tuberculosis Public Primary Patients in Three Districts, South Africa

    PubMed Central

    Peltzer, K; Mchunu, G; Tutshana, B; Naidoo, P; Matseke, G; Louw, J

    2012-01-01

    Background The acceptance of HIV testing among patients with tuberculosis (TB) is low in South Africa. The aim of this study was to assess the prevalence, associated factors and reasons of non-uptake of human immunodeficiency virus (HIV) testing by tuberculosis public primary care patients in three districts, South Africa. Methods: In May–October 2011, this cross-sectional survey was conducted amongst 4726 TB patients across 42 primary health care facilities in three districts in South Africa. All new TB and new retreatment patients (N=4726) were consecutively interviewed within one month of anti-tuberculosis treatment. The outcome was self-reported HIV testing after TB diagnosis, validated using clinic registers. Results: Almost one in ten (9.6%) of the 4726 participants had not undergone HIV testing, with the most often offered explanation being that they were not knowing where to get tested (21.3%), followed by believing not to have or at risk for HIV (24.3%), emotional concerns (not ready for test: 13.2%; afraid to get to know: 12.1%; concerns over confidentiality: 6.3%) and concerns about stigma (3.3%) and losing the job (2.0%). In multivariable analysis being male, severe psychological distress, having sex with someone HIV negative or unknown and frequency of sex without a condom were associated with not having been tested for HIV. Conclusions: The level of HIV testing among TB public primary care patients was suboptimal, as per policy all patients should be tested. The South African Department of Health should continue to scale-up HIV testing and other collaborative TB-HIV services at health facilities. PMID:23304672

  4. WS/PIDS: standard interoperable PIDS in web services environments.

    PubMed

    Vasilescu, E; Dorobanţu, M; Govoni, S; Padh, S; Mun, S K

    2008-01-01

    An electronic health record depends on the consistent handling of people's identities within and outside healthcare organizations. Currently, the Person Identification Service (PIDS), a CORBA specification, is the only well-researched standard that meets these needs. In this paper, we introduce WS/PIDS, a PIDS specification for Web Services (WS) that closely matches the original PIDS and improves on it by providing explicit support for medical multimedia attributes. WS/PIDS is currently supported by a test implementation, layered on top of a PIDS back-end, with Java- and NET-based, and Web clients. WS/PIDS is interoperable among platforms; it preserves PIDS semantics to a large extent, and it is intended to be fully compliant with established and emerging WS standards. The specification is open source and immediately usable in dynamic clinical systems participating in grid environments. WS/PIDS has been tested successfully with a comprehensive set of use cases, and it is being used in a clinical research setting. PMID:18270041

  5. Nef-Mediated Downregulation of CD4 Enhances Human Immunodeficiency Virus Type 1 Replication in Primary T Lymphocytes

    PubMed Central

    Lundquist, Christopher A.; Tobiume, Minoru; Zhou, Jing; Unutmaz, Derya; Aiken, Christopher

    2002-01-01

    The accessory protein Nef plays a crucial role in primate lentivirus pathogenesis. Nef enhances human immunodeficiency virus type 1 (HIV-1) infectivity in culture and stimulates viral replication in primary T cells. In this study, we investigated the relationship between HIV-1 replication efficiency in CD4+ T cells purified from human blood and two various known activities of Nef, CD4 downregulation and single-cycle infectivity enhancement. Using a battery of reporter viruses containing point mutations in nef, we observed a strong genetic correlation between CD4 downregulation by Nef during acute HIV-1 infection of activated T cells and HIV-1 replication efficiency in T cells. In contrast, HIV-1 replication ability was not significantly correlated with the ability of Nef to enhance single-cycle virion infectivity, as determined by using viruses produced in cells lacking CD4. These results demonstrate that CD4 downregulation by Nef plays a crucial role in HIV-1 replication in activated T cells and underscore the potential for the development of therapies targeting this conserved activity of Nef. PMID:11932428

  6. Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity

    PubMed Central

    Willmann, Katharina L.; Klaver, Stefanie; Doğu, Figen; Santos-Valente, Elisangela; Garncarz, Wojciech; Bilic, Ivan; Mace, Emily; Salzer, Elisabeth; Domínguez Conde, Cecilia; Sic, Heiko; Májek, Peter; Banerjee, Pinaki P.; Vladimer, Gregory I.; Haskoloğlu, Şule; Gökalp Bolkent, Musa; Küpesiz, Alphan; Condino-Neto, Antonio; Colinge, Jacques; Superti-Furga, Giulio; Pickl, Winfried F.; van Zelm, Menno C.; Eibel, Hermann; Orange, Jordan S.; Ikincioğulları, Aydan; Boztuğ, Kaan

    2014-01-01

    Primary immunodeficiency disorders enable identification of genes with crucial roles in the human immune system. Here we study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK (NF-κB-inducing kinase). Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling. Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression. Although overall T-cell numbers are normal, both follicular helper and memory T cells are perturbed. Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses. Collectively, our data illustrate the non-redundant role for NIK in human immune responses, demonstrating that loss-of-function mutations in NIK can cause multiple aberrations of lymphoid immunity. PMID:25406581

  7. Neutralizing Antibodies in Sera from Macaques Infected with Chimeric Simian-Human Immunodeficiency Virus Containing the Envelope Glycoproteins of either a Laboratory-Adapted Variant or a Primary Isolate of Human Immunodeficiency Virus Type 1

    PubMed Central

    Montefiori, David C.; Reimann, Keith A.; Wyand, Michael S.; Manson, Kelledy; Lewis, Mark G.; Collman, Ronald G.; Sodroski, Joseph G.; Bolognesi, Dani P.; Letvin, Norman L.

    1998-01-01

    The magnitude and breadth of neutralizing antibodies raised in response to infection with chimeric simian-human immunodeficiency virus (SHIV) in rhesus macaques were evaluated. Infection with either SHIV-HXB2, SHIV-89.6, or SHIV-89.6PD raised high-titer neutralizing antibodies to the homologous SHIV (SHIV-89.6P in the case of SHIV-89.6PD-infected animals) and significant titers of neutralizing antibodies to human immunodeficiency virus type 1 (HIV-1) strains MN and SF-2. With few exceptions, however, titers of neutralizing antibodies to heterologous SHIV were low or undetectable. The antibodies occasionally neutralized heterologous primary isolates of HIV-1; these antibodies required >40 weeks of infection to reach detectable levels. Notable was the potent neutralization of the HIV-1 89.6 primary isolate by serum samples from SHIV-89.6-infected macaques. These results demonstrate that SHIV-HXB2, SHIV-89.6, and SHIV-89.6P possess highly divergent, strain-specific neutralization epitopes. The results also provide insights into the requirements for raising neutralizing antibodies to primary isolates of HIV-1. PMID:9525675

  8. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases.

    PubMed

    Ochs, Hans D; Gupta, Sudhir; Kiessling, Peter; Nicolay, Uwe; Berger, Melvin

    2006-05-01

    Intravenous immunoglobulin (IVIg) infusions at 3-4 week intervals are currently standard therapy in the United States for patients with primary immune deficiency diseases (PIDD). To evaluate alternative modes of immunoglobulin administration we have designed an open-label study to investigate the efficacy and safety of a subcutaneously administered immunoglobulin preparation (16% IgG) in patients with PIDD. After their final IVIg infusion, 65 patients entered a 3-month, wash-in/wash-out phase, designed to bring patients to steady-state with subcutaneously administered immunoglobulin. This was followed by 12 months of weekly SCIg infusions, at a dose determined in a pharmacokinetic substudy to provide noninferior intravascular exposure. This resulted in a mean weekly dose of 158 mg/kg, calculated to equal 137% of the previous intravenous dose. Two patients (4%) each reported 1 serious bacterial infection (pneumonia), an annual rate of 0.04 per patient-year. There were 4.43 infections of any type per patient-year. Mean trough serum IgG levels increased from 786 to 1040 mg/dL during the study, a mean increase of 39%. The most frequent treatment-related adverse event was infusion-site reaction, reported by 91% of patients; this was predominantly mild or moderate, and the incidence decreased over time. No treatment-related serious adverse events were reported. We conclude that subcutaneous administration of 16% SCIg is a safe and effective alternative to IVIg for replacement therapy of PIDD. PMID:16783465

  9. [House calls to patients with an immunodeficiency disorder].

    PubMed

    Keestra, R W

    1988-10-01

    Eighty-seven patients with a primary immunodeficiency (PID) and their family doctors were interviewed on their opinions and experiences with the illness and the treatment. The aim of this inquiry was to gain insight in the problems that arise at home. Primary immunodeficiencies are rare and therefore unknown not only to the broad public, but also to many doctors. Patients experience much uncertainty about the character of their ailment, the risk of infections, the treatment possibilities and the prognosis. Information is greatly needed, but hardly available. Patients receive no written information on the subject from their specialists. The contact between PID patients and their family doctor is, generally speaking, poor. Treatment is done mainly on a (poli)clinical basis, leaving the family doctor out of the picture. Most patients say they would prefer home treatment; most family doctors say they would like to be more involved. The patient, however, is very often rushed to the hospital with the first symptoms of an infection. In this article it is argued why it is advisable to improve the contact between these patients and their family practitioners, even when the disease requires treatment by (super)specialists. In view of these facts and arguments it can be considered a challenge for the doctors at home and in the hospital to integrate both kinds of medical care, in order to prevent psychosocial disorders as a sequel of a somatic disease. The second part of the article deals with the setting up of an organisation of PID patients. Benefits of such an organisation, and also the possible risks involved, are discussed. PMID:3206519

  10. Vaccine-Elicited V3 Loop-Specific Antibodies in Rhesus Monkeys and Control of a Simian-Human Immunodeficiency Virus Expressing a Primary Patient Human Immunodeficiency Virus Type 1 Isolate Envelope

    PubMed Central

    Letvin, Norman L.; Robinson, Suzanne; Rohne, Daniela; Axthelm, Michael K.; Fanton, John W.; Bilska, Miroslawa; Palker, Thomas J.; Liao, Hua-Xin; Haynes, Barton F.; Montefiori, David C.

    2001-01-01

    Vaccine-elicited antibodies specific for the third hypervariable domain of the surface gp120 of human immunodeficiency virus type 1 (HIV-1) (V3 loop) were assessed for their contribution to protection against infection in the simian-human immunodeficiency virus (SHIV)/rhesus monkey model. Peptide vaccine-elicited anti-V3 loop antibody responses were examined for their ability to contain replication of SHIV-89.6, a nonpathogenic SHIV expressing a primary patient isolate HIV-1 envelope, as well as SHIV-89.6P, a pathogenic variant of that virus. Low-titer neutralizing antibodies to SHIV-89.6 that provided partial protection against viremia following SHIV-89.6 infection were generated. A similarly low-titer neutralizing antibody response to SHIV-89.6P that did not contain viremia after infection with SHIV-89.6P was generated, but a trend toward protection against CD4+ T-lymphocyte loss was seen in these infected monkeys. These observations suggest that the V3 loop on some primary patient HIV-1 isolates may be a partially effective target for neutralizing antibodies induced by peptide immunogens. PMID:11287566

  11. A formylpeptide receptor, FPRL1, acts as an efficient coreceptor for primary isolates of human immunodeficiency virus

    PubMed Central

    Shimizu, Nobuaki; Tanaka, Atsushi; Mori, Takahisa; Ohtsuki, Takahiro; Hoque, Aliful; Jinno-Oue, Atsushi; Apichartpiyakul, Chatchawann; Kusagawa, Shigeru; Takebe, Yutaka; Hoshino, Hiroo

    2008-01-01

    Background More than 10 members of seven-transmembrane G protein-coupled receptors (GPCRs) have been shown to work as coreceptors for human immunodeficiency virus type 1 (HIV-1), HIV type 2 (HIV-2), and simian immunodeficiency viruses (SIVs). As a common feature of HIV/SIV coreceptors, tyrosine residues are present with asparagines, aspartic acids or glutamic acids in the amino-terminal extracellular regions (NTRs). We noticed that a receptor for N-formylpeptides, FPRL1, also contains two tyrosine residues accompanied by glutamic acids in its NTR. It was reported that monocytes expressing CCR5 and FPRL1 in addition to CD4 are activated by treatment with ligands or agonists of FPRL1. Activated monocytes down-modulate CCR5 and become resistant to infection by HIV-1 strains. Thus, FPRL1 plays important roles in protection of monocyptes against HIV-1 infection. However, its own coreceptor activity has not been elucidated yet. In this study, we examined coreceptor activities of FPRL1 for HIV/SIV strains including primary HIV-1 isolates. Results A CD4-transduced human glioma cell line, NP-2/CD4, is strictly resistant to HIV/SIV infection. We have reported that when NP-2/CD4 cells are transduced with a GPCR having coreceptor activity, the cells become susceptible to HIV/SIV strains. When NP-2/CD4 cells were transduced with FPRL1, the resultant NP-2/CD4/FPRL1 cells became markedly susceptible to some laboratory-adapted HIV/SIV strains. We found that FPRL1 is also efficiently used as a coreceptor by primary HIV-1 isolates as well as CCR5 or CXCR4. Amino acid sequences linked to the FPRL1 use could not be detected in the V3 loop of the HIV-1 Env protein. Coreceptor activities of FPRL1 were partially blocked by the forymyl-Met-Leu-Phe (fMLF) peptide. Conclusion We conclude that FPRL1 is a novel and efficient coreceptor for HIV/SIV strains. FPRL1 works as a bifunctional factor in HIV-1 infection. Namely, the role of FPRL1 in HIV-1 infection is protective and/or promotive in

  12. Pharmacokinetics and safety of subcutaneous immune globulin (human), 10% caprylate/chromatography purified in patients with primary immunodeficiency disease

    PubMed Central

    Wasserman, R L; Irani, A-M; Tracy, J; Tsoukas, C; Stark, D; Levy, R; Chen, J; Sorrells, S; Roberts, R; Gupta, S

    2010-01-01

    Subcutaneous administration of intravenous immunoglobulin G (IgG) preparations provides an additional level of patient convenience and more options for patients with poor venous access or a history of intravenous IgG reactions. An open-label, pharmacokinetic trial (n = 32) determined the non-inferiority of the subcutaneous versus intravenous route of 10% caprylate/chromatography purified human immune globulin intravenous (IGIV-C; Gamunex®) administration by comparing the steady-state area under the concentration-versus-time curve (AUC) of total plasma IgG in patients with primary immunodeficiency disease. Patients on stable IGIV-C received two intravenous infusions (administered 3 or 4 weeks apart). Seven to 10 days after the second intravenous infusion, all patients switched to a weekly infusion of subcutaneous IGIV-C, with the dose equal to 137% of the previous weekly equivalent intravenous dose, for up to 24 weeks. Samples for pharmacokinetic analysis were collected during steady state for intravenous and subcutaneous IGIV-C treatments. The AUC0-τ geometric least-squares mean ratio was 0·89 (90% confidence interval, 0·86–0·92) and met the criteria for non-inferiority. The overall mean steady-state trough concentration of plasma total IgG with subcutaneous IGIV-C was 11·4 mg/ml, 18·8% higher than intravenous IGIV-C (9·6 mg/ml). Subcutaneous IGIV-C was safe and well tolerated. Subcutaneous IGIV-C infusion-site reactions were generally mild/moderate and the incidence decreased over time. No serious bacterial infections were reported. Weekly subcutaneous IGIV-C infusion using 137% of the weekly equivalent intravenous immunoglobulin dose provides an AUC comparable to intravenous administration, thus allowing patients to maintain the same IgG preparation/formulation if switching between intravenous and subcutaneous infusions. PMID:20550549

  13. The NF-kappa B binding site is necessary for efficient replication of simian immunodeficiency virus of macaques in primary macrophages but not in T cells in vitro.

    PubMed Central

    Bellas, R E; Hopkins, N; Li, Y

    1993-01-01

    We demonstrate here that the nuclear factor-kappa B (NF-kappa B) binding site in the simian immunodeficiency virus (SIVmac) long terminal repeat is essential for efficient virus replication in primary alveolar macrophages but dispensable for efficient replication in primary T cells. Mutation of the NF-kappa B site does not seriously impair replication of a T-cell-tropic SIVmac239 or a macrophagetropic SIVmacEm* in peripheral blood lymphocytes or established CD4+ cell lines; however, mutation of the NF-kappa B site prevents efficient SIVmacEm* replication in primary alveolar macrophages. These data suggest that efficient replication in primary macrophages requires both envelope and long terminal repeat determinants. Images PMID:8474179

  14. PID Tuning Using Extremum Seeking

    SciTech Connect

    Killingsworth, N; Krstic, M

    2005-11-15

    Although proportional-integral-derivative (PID) controllers are widely used in the process industry, their effectiveness is often limited due to poor tuning. Manual tuning of PID controllers, which requires optimization of three parameters, is a time-consuming task. To remedy this difficulty, much effort has been invested in developing systematic tuning methods. Many of these methods rely on knowledge of the plant model or require special experiments to identify a suitable plant model. Reviews of these methods are given in [1] and the survey paper [2]. However, in many situations a plant model is not known, and it is not desirable to open the process loop for system identification. Thus a method for tuning PID parameters within a closed-loop setting is advantageous. In relay feedback tuning [3]-[5], the feedback controller is temporarily replaced by a relay. Relay feedback causes most systems to oscillate, thus determining one point on the Nyquist diagram. Based on the location of this point, PID parameters can be chosen to give the closed-loop system a desired phase and gain margin. An alternative tuning method, which does not require either a modification of the system or a system model, is unfalsified control [6], [7]. This method uses input-output data to determine whether a set of PID parameters meets performance specifications. An adaptive algorithm is used to update the PID controller based on whether or not the controller falsifies a given criterion. The method requires a finite set of candidate PID controllers that must be initially specified [6]. Unfalsified control for an infinite set of PID controllers has been developed in [7]; this approach requires a carefully chosen input signal [8]. Yet another model-free PID tuning method that does not require opening of the loop is iterative feedback tuning (IFT). IFT iteratively optimizes the controller parameters with respect to a cost function derived from the output signal of the closed-loop system, see [9

  15. Use of V(D)J recombination excision circles to identify T- and B-cell defects and to monitor the treatment in primary and acquired immunodeficiencies

    PubMed Central

    2013-01-01

    T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) are circular DNA segments generated in T and B cells during their maturation in the thymus and bone marrow. These circularized DNA elements persist in the cells, are unable to replicate, and are diluted as a result of cell division, thus are considered markers of new lymphocyte output. The quantification of TRECs and KRECs, which can be reliably performed using singleplex or duplex real-time quantitative PCR, provides novel information in the management of T- and B-cell immunity-related diseases. In primary immunodeficiencies, when combined with flow cytometric analysis of T- and B-cell subpopulations, the measure of TRECs and KRECs has contributed to an improved characterization of the diseases, to the identification of patients’ subgroups, and to the monitoring of stem cell transplantation and enzyme replacement therapy. For the same diseases, the TREC and KREC assays, introduced in the newborn screening program, allow early disease identification and may lead to discovery of new genetic defects. TREC and KREC levels can also been used as a surrogate marker of lymphocyte output in acquired immunodeficiencies. The low number of TRECs, which has in fact been extensively documented in untreated HIV-infected subjects, has been shown to increase following antiretroviral therapy. Differently, KREC number, which is in the normal range in these patients, has been shown to decrease following long-lasting therapy. Whether changes of KREC levels have relevance in the biology and in the clinical aspects of primary and acquired immunodeficiencies remains to be firmly established. PMID:23656963

  16. Multivariable PID control by decoupling

    NASA Astrophysics Data System (ADS)

    Garrido, Juan; Vázquez, Francisco; Morilla, Fernando

    2016-04-01

    This paper presents a new methodology to design multivariable proportional-integral-derivative (PID) controllers based on decoupling control. The method is presented for general n × n processes. In the design procedure, an ideal decoupling control with integral action is designed to minimise interactions. It depends on the desired open-loop processes that are specified according to realisability conditions and desired closed-loop performance specifications. These realisability conditions are stated and three common cases to define the open-loop processes are studied and proposed. Then, controller elements are approximated to PID structure. From a practical point of view, the wind-up problem is also considered and a new anti-wind-up scheme for multivariable PID controller is proposed. Comparisons with other works demonstrate the effectiveness of the methodology through the use of several simulation examples and an experimental lab process.

  17. Pathway Interaction Database (PID) —

    Cancer.gov

    The National Cancer Institute (NCI) in collaboration with Nature Publishing Group has established the Pathway Interaction Database (PID) in order to provide a highly structured, curated collection of information about known biomolecular interactions and key cellular processes assembled into signaling pathways.

  18. Primary, syncytium-inducing human immunodeficiency virus type 1 isolates are dual-tropic and most can use either Lestr or CCR5 as coreceptors for virus entry.

    PubMed Central

    Simmons, G; Wilkinson, D; Reeves, J D; Dittmar, M T; Beddows, S; Weber, J; Carnegie, G; Desselberger, U; Gray, P W; Weiss, R A; Clapham, P R

    1996-01-01

    A panel of primary syncytium-inducing (SI) human immunodeficiency virus type 1 isolates that infected several CD4+ T-cell lines, including MT-2 and C8166, were tested for infection of blood-derived macrophages. Infectivity titers for C8166 cells and macrophages demonstrated that primary SI strains infected macrophages much more efficiently than T-cell line-adapted HIV-1 strains such as LAI and RF. These primary SI strains were therefore dual-tropic. Nine biological clones of two SI strains, prepared by limiting dilution, had macrophage/C8166 infectivity ratios similar to those of their parental viruses, indicating that the dual-tropic phenotype was not due to a mixture of non-SI/macrophage-tropic and SI/T-cell tropic viruses. We tested whether the primary SI strains used either Lestr (fusin) or CCR5 as coreceptors. Infection of cat CCC/CD4 cells transiently expressing Lestr supported infection by T-cell line-adapted strains including LAI, whereas CCC/CD4 cells expressing CCR5 were sensitive to primary non-SI strains as well as to the molecularly cloned strains SF-162 and JR-CSF. Several primary SI strains, as well as the molecularly cloned dual-tropic viruses 89.6 and GUN-1, infected both Lestr+ and CCR5+ CCC/CD4 cells. Thus, these viruses can choose between Lestr and CCR5 for entry into cells. Interestingly, some dual-tropic primary SI strains that infected Lestr+ cells failed to infect CCR5+ cells, suggesting that these viruses may use an alternative coreceptor for infection of macrophages. Alternatively, CCR5 may be processed or presented differently on cat cells so that entry of some primary SI strains but not others is affected. PMID:8970955

  19. Stem cell transplantation for the treatment of immunodeficiency in children: current status and hopes for the future.

    PubMed

    Booth, Claire; Silva, Juliana; Veys, Paul

    2016-07-01

    Primary immunodeficiencies (PID) are rare inherited disorders affecting immune function and can be life-threatening if not treated. Haematopoietic stem cell transplantation (HSCT) offers a curative approach for many of these disorders and gene therapy is increasingly used as an alternative therapeutic strategy for patients lacking a suitable donor. Early diagnosis, improved supportive care and advances in gene and cell therapies have resulted in increased survival rates and improved quality of life. This review describes current strategies employed to improve outcomes in PID, focusing on new developments in HSCT, gene and cell therapy. We also address the challenges associated with newborn screening (NBS) programmes and novel mutations identified through improved diagnostic technology. PMID:26882211

  20. Dissecting Epigenetic Dysregulation of Primary Antibody Deficiencies.

    PubMed

    Rodríguez-Cortez, Virginia C; Del Pino-Molina, Lucia; Rodríguez-Ubreva, Javier; López-Granados, Eduardo; Ballestar, Esteban

    2016-05-01

    Primary antibody deficiencies (PADs), the most prevalent inherited primary immunodeficiencies (PIDs), are associated with a wide range of genetic alterations (both monogenic or polygenic) in B cell-specific genes. However, correlations between the genotype and clinical manifestations are not evident in all cases indicating that genetic interactions, environmental and epigenetic factors may have a role in PAD pathogenesis. The recent identification of key defects in DNA methylation in common variable immunodeficiency as well as the multiple evidences on the role of epigenetic control during B cell differentiation, activation and during antibody formation highlight the importance of investing research efforts in dissecting the participation of epigenetic defects in this group of diseases. This review focuses on the role of epigenetic control in B cell biology which can provide clues for the study of potential novel pathogenic defects involved in PADs. PMID:26984849

  1. Immunodeficiency disorders

    MedlinePlus

    ... HIV in their immune systems and improve their immunity. People who are going to have a planned ... be used to treat certain immunodeficiency conditions. Passive immunity (receiving antibodies produced by another person or animal) ...

  2. Immunodeficiency disorders

    MedlinePlus

    ... HIV in their immune systems and improve their immunity. Patients who are going to have a planned ... be used to treat certain immunodeficiency conditions. Passive immunity (receiving antibodies produced by another person or animal) ...

  3. A Comparative Study of Intravenous Immunoglobulin and Subcutaneous Immunoglobulin in Adult Patients with Primary Immunodeficiency Diseases: A Systematic Review and Meta-Analysis.

    PubMed

    Shabaninejad, Hosein; Asgharzadeh, Asra; Rezaei, Nima; Rezapoor, Aziz

    2016-05-01

    Subcutaneous immunoglobulin (SCIG) is a new therapeutic procedure for patients with primary immunodeficiency (PI). This research is a systematic review of studies on the efficacy and safety of intravenous immunoglobulin (IVIG) and SCIG in adult patients with PI. This study includes a systematic review of cohorts and randomized clinical trials (24 articles) from 5 databases with no time limits. Random effects meta-analysis was performed for outcomes such as efficacy and safety. Standard mean difference (SMD) of serum immunoglobulin level was equal to 0.336 (P <0.01; 0.205-0.467) and the odds ratio (OR) of side effects was 0.497 (P=0.1; 0.180-1.371). The results indicate that SCIG leads to a higher level of immunoglobulin and a reduction in side effects but shows the same infection rate as IVIG. Our analysis shows that shifting from IVIG to SCIG therapy can have clinical benefits for PI patients. PMID:26902306

  4. Interaction of nuclear protein p140 with human immunodeficiency virus type 1 TAR RNA in mitogen-activated primary human T lymphocytes.

    PubMed Central

    Rothblum, C J; Jackman, J; Mikovits, J; Shukla, R R; Kumar, A

    1995-01-01

    Several lines of evidence suggest that cellular proteins play a role during human immunodeficiency virus type 1 (HIV-1) Tat-mediated trans activation. A recent report from this laboratory has shown that a 140-kDa HeLa nuclear protein (p140) binds specifically to the lower stem region of the Tat response element, TAR RNA. Since HIV-1 trans activation is most efficient in proliferating T cells, we investigated the binding of p140 to TAR RNA in unstimulated and mitogen-activated, G1-phase primary T lymphocytes. TAR RNA/protein-binding activity was low in resting cells but increased significantly within 2 h of activation and remained elevated for at least 48 h. Corresponding increases in p140 protein levels were observed with most but not all donors, suggesting that an additional nuclear factor(s) may be required for efficient binding of this protein to TAR RNA in activated T cells. PMID:7609087

  5. Cell Cycle- and Vpr-Mediated Regulation of Human Immunodeficiency Virus Type 1 Expression in Primary and Transformed T-Cell Lines

    PubMed Central

    Gummuluru, Suryaram; Emerman, Michael

    1999-01-01

    Viral protein R (Vpr) of human immunodeficiency virus type 1 (HIV-1) transiently arrests cells in the G2 phase of the cell cycle and is a weak transcriptional transactivator. We found that Vpr increased HIV-1 long terminal repeat (LTR) activity in all cells examined but, when expressed at high levels, decreased HIV-1 LTR expression due to cytotoxic effects. Moreover, Vpr-mediated enhancement of HIV-1 LTR-driven transcription was observed in cycling primary human CD4+ T cells but not in terminally differentiated, noncycling primary human macrophages. In single-round infection experiments using primary human CD4+ T cells, proviral clones expressing either wild-type Vpr or Vpr mutants that retained the ability to cause a G2 arrest replicated to higher levels than proviruses lacking Vpr or expressing mutants of Vpr that did not cause an arrest. In support of the hypothesis that enhancement of HIV-1 LTR transcription by Vpr is an indirect effect of the ability of Vpr to delay cells in G2, counterflow centrifugal elutriation of cells into different phases of the cell cycle demonstrated that HIV-1 LTR expression was highest in G2. Finally, the ability of Vpr to upregulate viral transcription was dependent on a minimal promoter containing a functional TATA box and an enhancer. PMID:10364289

  6. Antibodies with specificity to native gp120 and neutralization activity against primary human immunodeficiency virus type 1 isolates elicited by immunization with oligomeric gp160.

    PubMed Central

    VanCott, T C; Mascola, J R; Kaminski, R W; Kalyanaraman, V; Hallberg, P L; Burnett, P R; Ulrich, J T; Rechtman, D J; Birx, D L

    1997-01-01

    Current human immunodeficiency virus type 1 (HIV-1) envelope vaccine candidates elicit high antibody binding titers with neutralizing activity against T-cell line-adapted but not primary HIV-1 isolates. Serum antibodies from these human vaccine recipients were also found to be preferentially directed to linear epitopes within gp120 that are poorly exposed on native gp120. Systemic immunization of rabbits with an affinity-purified oligomeric gp160 protein formulated with either Alhydrogel or monophosphoryl lipid A-containing adjuvants resulted in the induction of high-titered serum antibodies that preferentially bound epitopes exposed on native forms of gp120 and gp160, recognized a restricted number of linear epitopes, efficiently bound heterologous strains of monomeric gp120 and cell surface-expressed oligomeric gp120/gp41, and neutralized several strains of T-cell line-adapted HIV-1. Additionally, those immune sera with the highest oligomeric gp160 antibody binding titers had neutralizing activity against some primary HIV-1 isolates, using phytohemagglutinin-stimulated peripheral blood mononuclear cell targets. Induction of an antibody response preferentially reactive with natively folded gp120/gp160 was dependent on the tertiary structure of the HIV-1 envelope immunogen as well as its adjuvant formulation, route of administration, and number of immunizations administered. These studies demonstrate the capacity of a soluble HIV-1 envelope glycoprotein vaccine to elicit an antibody response capable of neutralizing primary HIV-1 isolates. PMID:9151820

  7. Natural History of Primary Epstein-Barr Virus Infection in Children of Mothers Infected with Human Immunodeficiency Virus Type 1

    PubMed Central

    Jenson, Hal; McIntosh, Kenneth; Pitt, Jane; Husak, Scott; Tan, Ming; Bryson, Yvonne; Easley, Kirk

    2015-01-01

    The natural history of Epstein-Barr virus (EBV) infection in 556 infants born to 517 human immunodeficiency virus (HIV) type 1–infected mothers was studied in a prospective, multicenter, cohort study. HIV-1–infected children had a cumulative EBV infection rate similar to HIV-1–uninfected children at age 3 years (77.8% vs. 84.9%) but had more frequent oropharyngeal EBV shedding (50.4% vs. 28.2%; P < .001). The probability of shedding decreased with longer time from EBV seroconversion and was similar to that of HIV-1–uninfected children 3 years after seroconversion. HIV-1–infected children identified as rapid progressors shed EBV more frequently than nonrapid progressors (69.4% vs.41.0%; P = .01). HIV-1–infected children with EBV infection had higher mean CD8 cell counts. EBV infection did not have an independent effect on mean CD4 cell counts, percent CD4, IgG levels, HIV-1 RNA levels, lymphadenopathy, hepatomegaly, or splenomegaly. Early EBV infection is common in children born to HIV-1–infected mothers. Children with rapidly progressive HIV-1 disease have more frequent EBV shedding. PMID:10228060

  8. Divergent Kinetics of Proliferating T Cell Subsets in Simian Immunodeficiency Virus (SIV) Infection: SIV Eliminates the “First Responder” CD4+ T Cells in Primary Infection

    PubMed Central

    Wang, Xiaolei; Xu, Huanbin; Pahar, Bapi; Lackner, Andrew A.

    2013-01-01

    Although increased lymphocyte turnover in chronic human immunodeficiency virus and simian immunodeficiency virus (SIV) infection has been reported in blood, there is little information on cell turnover in tissues, particularly in primary SIV infection. Here we examined the levels of proliferating T cell subsets in mucosal and peripheral lymphoid tissues of adult macaques throughout SIV infection. To specifically label cells in S-phase division, all animals were inoculated with bromodeoxyuridine 24 h prior to sampling. In healthy macaques, the highest levels of proliferating CD4+ and CD8+ T cells were in blood and, to a lesser extent, in spleen. Substantial percentages of proliferating cells were also found in intestinal tissues, including the jejunum, ileum, and colon, but very few proliferating cells were detected in lymph nodes (axillary and mesenteric). Moreover, essentially all proliferating T cells in uninfected animals coexpressed CD95 and many coexpressed CCR5 in the tissues examined. Confocal microscopy also demonstrated that proliferating cells were substantial viral target cells for SIV infection and viral replication. After acute SIV infection, percentages of proliferating CD4+ and CD8+ T cells were significantly higher in tissues of chronically infected macaques and macaques with AIDS than in those of the controls. Surprisingly, however, we found that proliferating CD4+ T cells were selectively decreased in very early infection (8 to 10 days postinoculation [dpi]). In contrast, levels of proliferating CD8+ T cells rapidly increased after SIV infection, peaked by 13 to 21 dpi, and thereafter remained significantly higher than those in the controls. Taken together, these findings suggest that SIV selectively infects and destroys dividing, nonspecific CD4+ T cells in acute infection, resulting in homeostatic changes and perhaps continuing loss of replication capacity to respond to nonspecific and, later, SIV-specific antigens. PMID:23596288

  9. Efficacy and safety of subcutaneous vivaglobin® replacement therapy in previously untreated patients with primary immunodeficiency: a prospective, multicenter study.

    PubMed

    Borte, Michael; Quinti, Isabella; Soresina, Annarosa; Fernández-Cruz, Eduardo; Ritchie, Bruce; Schmidt, Dirk S; McCusker, Christine

    2011-12-01

    Treatment of primary immunodeficiency (PI) is typically initiated with intravenous immunoglobulin (IVIG) loading and then continued with IVIG or subcutaneous IgG (SCIG). This prospective, open-label, multicenter, 6-month study evaluated a new regimen of initiating IgG therapy with SCIG in 18 previously untreated patients. In the loading phase, SCIG 100 mg/kg was administered for five consecutive days (total loading dose 500 mg/kg). During the maintenance phase, patients self-infused SCIG 100 mg/kg/week at home. The primary efficacy endpoint of IgG levels ≥5 g/L on day 12 was achieved in 17 patients (94.4%; 95% CI 0.727, 0.999). The rate of infections was 3.95 episodes/patient/year. Improvement was found in many subscales of the health-related quality of life questionnaires. SCIG treatment was well tolerated, with no related serious adverse events (AEs). Nine (50%) patients experienced related AEs, including local reactions (rate 0.105 events/infusion). The results suggest that therapy of newly diagnosed patients with PI can be initiated directly with SCIG. PMID:21932110

  10. Convergence performance comparisons of PID, MRAC, and PID + MRAC hybrid controller

    NASA Astrophysics Data System (ADS)

    Zhang, Dan; Wei, Bin

    2016-05-01

    This study proposes a hybrid controller by combining a proportional-integral-derivative (PID) control and a model reference adaptive control (MRAC), which named as PID + MRAC controller. The convergence performances of the PID control, MRAC, and hybrid PID + MRAC are also compared. Through the simulation in Matlab, the results show that the convergence speed and performance of the MRAC and the PID + MRAC controller are better than those of the PID controller. In addition, the convergence performance of the hybrid control is better than that of the MRAC control.

  11. Convergence performance comparisons of PID, MRAC, and PID + MRAC hybrid controller

    NASA Astrophysics Data System (ADS)

    Zhang, Dan; Wei, Bin

    2016-06-01

    This study proposes a hybrid controller by combining a proportional-integral-derivative (PID) control and a model reference adaptive control (MRAC), which named as PID + MRAC controller. The convergence performances of the PID control, MRAC, and hybrid PID + MRAC are also compared. Through the simulation in Matlab, the results show that the convergence speed and performance of the MRAC and the PID + MRAC controller are better than those of the PID controller. In addition, the convergence performance of the hybrid control is better than that of the MRAC control.

  12. Calculating the Dose of Subcutaneous Immunoglobulin for Primary Immunodeficiency Disease in Patients Switched From Intravenous to Subcutaneous Immunoglobulin Without the Use of a Dose-Adjustment Coefficient

    PubMed Central

    Fadeyi, Michael; Tran, Tin

    2013-01-01

    Primary immunodeficiency disease (PIDD) is an inherited disorder characterized by an inadequate immune system. The most common type of PIDD is antibody deficiency. Patients with this disorder lack the ability to make functional immunoglobulin G (IgG) and require lifelong IgG replacement therapy to prevent serious bacterial infections. The current standard therapy for PIDD is intravenous immunoglobulin (IVIG) infusions, but IVIG might not be appropriate for all patients. For this reason, subcutaneous immunoglobulin (SCIG) has emerged as an alternative to IVIG. A concern for physicians is the precise SCIG dose that should be prescribed, because there are pharmacokinetic differences between IVIG and SCIG. Manufacturers of SCIG 10% and 20% liquid (immune globulin subcutaneous [human]) recommend a dose-adjustment coefficient (DAC). Both strengths are currently approved by the FDA. This DAC is to be used when patients are switched from IVIG to SCIG. In this article, we propose another dosing method that uses a higher ratio of IVIG to SCIG and an incremental adjustment based on clinical status, body weight, and the presence of concurrent diseases. PMID:24391400

  13. A Cell Line-Based Neutralization Assay for Primary Human Immunodeficiency Virus Type 1 Isolates That Use either the CCR5 or the CXCR4 Coreceptor

    PubMed Central

    Trkola, Alexandra; Matthews, Jamie; Gordon, Cynthia; Ketas, Tom; Moore, John P.

    1999-01-01

    We describe here a cell line-based assay for the evaluation of human immunodeficiency virus type 1 (HIV-1) neutralization. The assay is based on CEM.NKR cells, transfected to express the HIV-1 coreceptor CCR5 to supplement the endogenous expression of CD4 and the CXCR4 coreceptor. The resulting CEM.NKR-CCR5 cells efficiently replicate primary HIV-1 isolates of both R5 and X4 phenotypes. A comparison of the CEM.NKR-CCR5 cells with mitogen-activated peripheral blood mononuclear cells (PBMC) in neutralization assays with sera from HIV-1-infected individuals or specific anti-HIV-1 monoclonal antibodies shows that the sensitivity of HIV-1 neutralization is similar in the two cell types. The CEM.NKR-CCR5 cell assay, however, is more convenient to perform and eliminates the donor-to-donor variation in HIV-1 replication efficiency, which is one of the principal drawbacks of the PBMC-based neutralization assay. We suggest that this new assay is suitable for the general measurement of HIV-1 neutralization by antibodies. PMID:10516002

  14. gp340 Promotes Transcytosis of Human Immunodeficiency Virus Type 1 in Genital Tract-Derived Cell Lines and Primary Endocervical Tissue▿

    PubMed Central

    Stoddard, Earl; Ni, Houping; Cannon, Georgetta; Zhou, Chunhui; Kallenbach, Neville; Malamud, Daniel; Weissman, Drew

    2009-01-01

    The human scavenger receptor gp340 has been identified as a binding protein for the human immunodeficiency virus type 1 (HIV-1) envelope that is expressed on the cell surface of female genital tract epithelial cells. This interaction allows such epithelial cells to efficiently transmit infective virus to susceptible targets and maintain viral infectivity for several days. Within the context of vaginal transmission, HIV must first traverse a normally protective mucosa containing a cell barrier to reach the underlying T cells and dendritic cells, which propagate and spread the infection. The mechanism by which HIV-1 can bypass an otherwise healthy cellular barrier remains an important area of study. Here, we demonstrate that genital tract-derived cell lines and primary human endocervical tissue can support direct transcytosis of cell-free virus from the apical to basolateral surfaces. Further, this transport of virus can be blocked through the addition of antibodies or peptides that directly block the interaction of gp340 with the HIV-1 envelope, if added prior to viral pulsing on the apical side of the cell or tissue barrier. Our data support a role for the previously described heparan sulfate moieties in mediating this transcytosis but add gp340 as an important facilitator of HIV-1 transcytosis across genital tract tissue. This study demonstrates that HIV-1 actively traverses the protective barriers of the human genital tract and presents a second mechanism whereby gp340 can promote heterosexual transmission. PMID:19553331

  15. Use of a heminested reverse transcriptase PCR assay for detection of astrovirus in environmental swabs from an outbreak of gastroenteritis in a pediatric primary immunodeficiency unit.

    PubMed

    Gallimore, Chris I; Taylor, Clive; Gennery, Andrew R; Cant, Andrew J; Galloway, Angela; Lewis, David; Gray, Jim J

    2005-08-01

    An outbreak of astrovirus gastroenteritis occurred in the Primary Immunodeficiency Unit at Newcastle General Hospital in March 2004. Environmental swabbing of the unit was undertaken after the outbreak, with multiple sites swabbed pre- and postcleaning. Astroviruses were detected in four environmental swabs and from two patient fecal samples using heminested reverse transcriptase PCR. An astrovirus genotype 3 strain was identified in both environmental swabs and fecal specimens and was the strain identified as being responsible for the outbreak. Environmental transmission of the virus was thought to have occurred by contamination of a syringe pump outside the laminar-flow curtain of a patient who was admitted with astrovirus gastroenteritis. This was subsequently transmitted to a cubicle next door and to a television/games console in a parents' room in the ward. Environmental monitoring of surfaces/equipment, using PCR assays for gastroenteric viruses in hospital situations where infection can give rise to serious clinical complications, may have a role in controlling and monitoring cleaning and the subsequent prevention of nosocomial transmission of gastroenteritis. PMID:16081927

  16. Human Immunodeficiency Virus Prevention.

    PubMed

    Davis, Teaniese Latham; DiClemente, Ralph

    2016-04-01

    Human immunodeficiency virus (HIV) is the virus that causes AIDS. Surveillance data from 2012 indicate an estimated 1.2 million people aged 13 years and older were living with HIV infection in the United States, and 12.8% do not know their status. There are approximately 50,000 new HIV infections annually. With no available cure for HIV, primary prevention to reduce incident cases of HIV is essential. Strategies to prevent HIV transmission include reducing sexual risk behavior and needle sharing. The Centers for Disease Control and Prevention has multiple resources available for primary and secondary prevention to reduce disease transmission and severity. PMID:26980130

  17. Primary Immune Deficiency Treatment Consortium (PIDTC) Report

    PubMed Central

    Griffith, Linda M.; Cowan, Morton J.; Notarangelo, Luigi D.; Kohn, Donald B.; Puck, Jennifer M.; Pai, Sung-Yun; Ballard, Barbara; Bauer, Sarah C.; Bleesing, Jack J. H.; Boyle, Marcia; Brower, Amy; Buckley, Rebecca H.; van der Burg, Mirjam; Burroughs, Lauri M.; Candotti, Fabio; Cant, Andrew J.; Chatila, Talal; Cunningham-Rundles, Charlotte; Dinauer, Mary C.; Dvorak, Christopher C.; Filipovich, Alexandra H.; Fleisher, Thomas A.; Gaspar, Hubert Bobby; Gungor, Tayfun; Haddad, Elie; Hovermale, Emily; Huang, Faith; Hurley, Alan; Hurley, Mary; Iyengar, Sumathi; Kang, Elizabeth M.; Logan, Brent R.; Long-Boyle, Janel R.; Malech, Harry L.; McGhee, Sean A.; Modell, Fred; Modell, Vicki; Ochs, Hans D.; O'Reilly, Richard J.; Parkman, Robertson; Rawlings, David J.; Routes, John M.; Shearer, William T.; Small, Trudy N.; Smith, Heather; Sullivan, Kathleen E.; Szabolcs, Paul; Thrasher, Adrian; Torgerson, Troy R.; Veys, Paul; Weinberg, Kenneth; Zuniga-Pflucker, Juan Carlos

    2013-01-01

    The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases (PID). Current protocols address the natural history of patients treated for Severe Combined Immunodeficiency (SCID), Wiskott-Aldrich Syndrome and Chronic Granulomatous Disease through retrospective, prospective and cross-sectional studies. The PIDTC additionally seeks to: encourage training of junior investigators; establish partnerships with European and other International colleagues; work with patient advocacy groups to promote community awareness; and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for PID. To date, the PIDTC has funded two pilot projects: newborn screening for SCID in Navajo Native Americans; and B cell reconstitution in SCID patients following hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first two PIDTC workshops, and consideration of future consortium objectives. PMID:24139498

  18. Macrophages and CD4+ T lymphocytes from two multiply exposed, uninfected individuals resist infection with primary non-syncytium-inducing isolates of human immunodeficiency virus type 1.

    PubMed Central

    Connor, R I; Paxton, W A; Sheridan, K E; Koup, R A

    1996-01-01

    Despite multiple, high-risk sexual exposures, some individuals remain uninfected with human immunodeficiency virus type 1 (HIV-1). CD4+ lymphocytes from these individuals are less susceptible to infection in vitro with some strains of HIV-1, suggesting that the phenotype of the virus may influence its ability to interact with certain CD4+ cells. In the present study, we examined the susceptibility of CD4+ T lymphocytes and macrophages from two exposed uninfected individuals (EU2 and EU3) to infection with a panel of biologically cloned isolates of HIV-1 having either a non-syncytium-inducing (NSI) or a syncytium-inducing (SI) phenotype. Our results indicate that CD4+ T lymphocytes from EU2 and EU3 are resistant to infection with NSI isolates of HIV-1 but are susceptible to infection with primary SI isolates. In addition, we found that macrophages from EU2 and EU3 are resistant to infection with both NSI and SI isolates. The latter finding was confirmed by using several uncloned NSI and SI isolates obtained from patients during acute HIV-1 infection. In further experiments, env clones encoding glycoproteins characteristic of NSI or SI viruses were used in single-cycle infectivity assays to evaluate infection of CD4+ lymphocytes and macrophages from EU2 and EU3. Consistent with our previous results, we found that macrophages from these individuals are resistant to infection with NSI and SI env-pseudotyped viruses, while CD4+ T lymphocytes are resistant to NSI, but not SI, pseudotyped viruses. Overall, our results demonstrate that CD4+ cells from two exposed uninfected individuals resist infection in vitro with primary, macrophage-tropic, NSI isolates of HIV-1, which is the predominant viral phenotype found following HIV-1 transmission. Furthermore, infection with NSI isolates was blocked in both CD4+ T lymphocytes and macrophages from these individuals, suggesting that there may be a common mechanism for resistance in both cell types. PMID:8971004

  19. An early defect in primary and secondary T cell responses in asymptomatic cats during acute feline immunodeficiency virus (FIV) infection.

    PubMed Central

    Bishop, S A; Williams, N A; Gruffydd-Jones, T J; Harbour, D A; Stokes, C R

    1992-01-01

    As in HIV infection of humans, cats infected with FIV are particularly susceptible to secondary infection by opportunistic pathogens, suggesting an impaired ability to elicit an effective immune response against foreign antigens. In order to investigate the development of immunity in FIV-infected cats, we have used an autologous culture system to directly measure priming of naive CD4+ T cells to soluble protein antigen, in vitro. Using this assay, we showed previously that cats infected with FIV for several months had significantly reduced primary proliferative responses. We have now examined cats before infection, and at varying times after infection with FIV, to determine how soon after infection this defect in T cell priming was evident, compared with other quantitative and qualitative measurements of lymphocyte function. Our results showed a progressive decline in immune function in asymptomatic cats during the acute stage of infection with FIV. Primary T cell responses were most sensitive and a significant reduction in proliferation of naive T cells to foreign antigen occurred 5 weeks after infection, despite normal blastogenesis to T cell mitogens and normal CD4+/CD8+ ratios at these times. Whilst lymphocyte proliferation to T cell mitogens was unaffected throughout, a significant reduction in proliferation to a B cell mitogen occurred from week 8 onwards. CD4+/CD8+ ratios fell significantly from week 13 onwards, and proliferation of the memory T cell population to a recall antigen was significantly impaired later, from week 19 onwards. The defect in the priming of naive T cells to foreign antigen early after infection may be important in determining susceptibility to secondary infections. PMID:1458687

  20. The case for a national service for primary immune deficiency disorders in New Zealand.

    PubMed

    Ameratunga, Rohan; Steele, Richard; Jordan, Anthony; Preece, Kahn; Barker, Russell; Brewerton, Maia; Lindsay, Karen; Sinclair, Jan; Storey, Peter; Woon, See-Tarn

    2016-01-01

    Primary immune deficiency disorders (PIDs) are rare conditions for which effective treatment is available. It is critical these patients are identified at an early stage to prevent unnecessary morbidity and mortality. Treatment of these disorders is expensive and expert evaluation and ongoing management by a clinical immunologist is essential. Until recently there has been a major shortage of clinical immunologists in New Zealand. While the numbers of trained immunologists have increased in recent years, most are located in Auckland. The majority of symptomatic PID patients require life-long immunoglobulin replacement. Currently there is a shortage of subcutaneous and intravenous immunoglobulin (SCIG/IVIG) in New Zealand. A recent audit by the New Zealand Blood Service (NZBS) showed that compliance with indications for SCIG/IVIG treatment was poor in District Health Boards (DHBs) without an immunology service. The NZBS audit has shown that approximately 20% of annual prescriptions for SCIG/IVIG, costing $6M, do not comply with UK or Australian guidelines. Inappropriate use may have contributed to the present shortage of SCIG/IVIG necessitating importation of the product. This is likely to have resulted in a major unnecessary financial burden to each DHB. Here we present the case for a national service responsible for the tertiary care of PID patients and oversight for immunoglobulin use for primary and non-haematological secondary immunodeficiencies. We propose that other PIDs, including hereditary angioedema, are integrated into a national PID service. Ancillary services, including the customised genetic testing service, and research are also an essential component of an integrated national PID service and are described in this review. As we show here, a hub-and-spoke model for a national service for PIDs would result in major cost savings, as well as improved patient care. It would also allow seamless transition from paediatric to adult services. PMID:27355232

  1. Current treatment options with immunoglobulin G for the individualization of care in patients with primary immunodeficiency disease1

    PubMed Central

    Jolles, S; Orange, J S; Gardulf, A; Stein, M R; Shapiro, R; Borte, M; Berger, M

    2015-01-01

    Primary antibody deficiencies require lifelong replacement therapy with immunoglobulin (Ig)G to reduce the incidence and severity of infections. Both subcutaneous and intravenous routes of administering IgG can be effective and well tolerated. Treatment regimens can be individualized to provide optimal medical and quality-of-life outcomes in infants, children, adults and elderly people. Frequency, dose, route of administration, home or infusion-centre administration, and the use of self- or health-professional-administered infusion can be tailored to suit individual patient needs and circumstances. Patient education is needed to understand the disease and the importance of continuous therapy. Both the subcutaneous and intravenous routes have advantages and disadvantages, which should be considered in selecting each patient's treatment regimen. The subcutaneous route is attractive to many patients because of a reduced incidence of systemic adverse events, flexibility in scheduling and its comparative ease of administration, at home or in a clinic. Self-infusion regimens, however, require independence and self-reliance, good compliance on the part of the patient/parent and the confidence of the physician and the nurse. Intravenous administration in a clinic setting may be more appropriate in patients with reduced manual dexterity, reluctance to self-administer or a lack of self-reliance, and intravenous administration at home for those with good venous access who prefer less frequent treatments. Both therapy approaches have been demonstrated to provide protection from infections and improve health-related quality of life. Data supporting current options in IgG replacement are presented, and considerations in choosing between the two routes of therapy are discussed. PMID:25384609

  2. Detection of Candida dubliniensis in Oropharyngeal Samples from Human Immunodeficiency Virus-Infected Patients in North America by Primary CHROMagar Candida Screening and Susceptibility Testing of Isolates

    PubMed Central

    Kirkpatrick, William R.; Revankar, Sanjay G.; Mcatee, Robert K.; Lopez-Ribot, Jose L.; Fothergill, Annette W.; McCarthy, Dora I.; Sanche, Stephen E.; Cantu, Rebecca A.; Rinaldi, Michael G.; Patterson, Thomas F.

    1998-01-01

    Candida dubliniensis has been associated with oropharyngeal candidiasis in patients infected with human immunodeficiency virus (HIV). C. dubliniensis isolates may have been improperly characterized as atypical Candida albicans due to the phenotypic similarity between the two species. Prospective screening of oral rinses from 63 HIV-infected patients detected atypical dark green isolates on CHROMagar Candida compared to typical C. albicans isolates, which are light green. Forty-eight atypical isolates and three control strains were characterized by germ tube formation, differential growth at 37, 42, and 45°C, identification by API 20C, fluorescence, chlamydoconidium production, and fingerprinting by Ca3 probe DNA hybridization patterns. All isolates were germ tube positive. Very poor or no growth occurred at 42°C with 22 of 51 isolates. All 22 poorly growing isolates at 42°C and one isolate with growth at 42°C showed weak hybridization of the Ca3 probe with genomic DNA, consistent with C. dubliniensis identification. No C. dubliniensis isolate but only 18 of 28 C. albicans isolates grew at 45°C. Other phenotypic or morphologic tests were less reliable in differentiating C. dubliniensis from C. albicans. Antifungal susceptibility testing showed fluconazole MICs ranging from ≤0.125 to 64 μg/ml. Two isolates were resistant to fluconazole (MIC, 64 μg/ml) and one strain was dose dependent susceptible (MIC, 16 μg/ml). MICs of other azoles, including voriconazole, itraconazole, and SCH 56592, for these isolates were lower. C. dubliniensis was identified in 11 of 63 (17%) serially evaluated patients. Variability in phenotypic characteristics dictates the use of molecular and biochemical techniques to identify C. dubliniensis. This study identifies C. dubliniensis in HIV-infected patients from San Antonio, Tex., and shows that C. dubliniensis is frequently detected in those patients by using a primary CHROMagar screen. PMID:9738058

  3. Subcutaneous immunoglobulin (16 or 20%) therapy in obese patients with primary immunodeficiency: a retrospective analysis of administration by infusion pump or subcutaneous rapid push.

    PubMed

    Shapiro, R

    2013-08-01

    A retrospective chart review was conducted at a single centre, capturing data on 173 primary immunodeficiency disease (PIDD) patients, including 40 obese patients, using subcutaneous administration of immunoglobulin (Ig) (SCIG) (16 or 20%) delivered by infusion pump or subcutaneous (s.c.) rapid push. Patients previously using Ig administered as intravenous (i.v.) infusions (IVIG) were converted to SCIG dosing on a 1:1 basis. In both obese and non-obese patients, mean serum Ig levels were higher during SCIG administration (steady state) compared with IVIG administration (trough values). Similar SCIG dose : serum IgG level relationships were observed between obese and non-obese patients, suggesting the consistent bioavailability of SCIG regardless of body mass index (BMI). The mean SCIG volume per dosing site and the mean number of dosing days per week were greater with s.c. rapid push compared with infusion pump in this cohort, but the mean number of sites per infusion session was lower with s.c. rapid push. Both methods were well tolerated. The use of 20 versus 16% SCIG in obese patients improved dosing efficiency, resulting in smaller weekly volumes (54·7 versus 74·5 ml/week) and dosing on fewer days per week (2·3 versus 3·4 days). These data do not suggest a need for SCIG dosing adjustments in obese individuals relative to non-obese patients. The administration of SCIG using either infusion pump or s.c. rapid push is a practical and well-tolerated alternative to IVIG in obese patients. Offering various administration techniques provides a greater opportunity for treatment satisfaction and patient empowerment, which may support high levels of patient compliance. PMID:23607310

  4. Subcutaneous immunoglobulin (16 or 20%) therapy in obese patients with primary immunodeficiency: a retrospective analysis of administration by infusion pump or subcutaneous rapid push

    PubMed Central

    Shapiro, R

    2013-01-01

    A retrospective chart review was conducted at a single centre, capturing data on 173 primary immunodeficiency disease (PIDD) patients, including 40 obese patients, using subcutaneous administration of immunoglobulin (Ig) (SCIG) (16 or 20%) delivered by infusion pump or subcutaneous (s.c.) rapid push. Patients previously using Ig administered as intravenous (i.v.) infusions (IVIG) were converted to SCIG dosing on a 1:1 basis. In both obese and non-obese patients, mean serum Ig levels were higher during SCIG administration (steady state) compared with IVIG administration (trough values). Similar SCIG dose : serum IgG level relationships were observed between obese and non-obese patients, suggesting the consistent bioavailability of SCIG regardless of body mass index (BMI). The mean SCIG volume per dosing site and the mean number of dosing days per week were greater with s.c. rapid push compared with infusion pump in this cohort, but the mean number of sites per infusion session was lower with s.c. rapid push. Both methods were well tolerated. The use of 20 versus 16% SCIG in obese patients improved dosing efficiency, resulting in smaller weekly volumes (54·7 versus 74·5 ml/week) and dosing on fewer days per week (2·3 versus 3·4 days). These data do not suggest a need for SCIG dosing adjustments in obese individuals relative to non-obese patients. The administration of SCIG using either infusion pump or s.c. rapid push is a practical and well-tolerated alternative to IVIG in obese patients. Offering various administration techniques provides a greater opportunity for treatment satisfaction and patient empowerment, which may support high levels of patient compliance. PMID:23607310

  5. Chronic granulomatous disease: a 25-year patient registry based on a multistep diagnostic procedure, from the referral center for primary immunodeficiencies in Greece.

    PubMed

    Raptaki, Maria; Varela, Ioanna; Spanou, Kleopatra; Tzanoudaki, Marianna; Tantou, Sofia; Liatsis, Manolis; Constantinidou, Nikki; Bakoula, Chryssa; Roos, Dirk; Kanariou, Maria

    2013-11-01

    Chronic Granulomatous Disease (CGD) is an uncommon primary immunodeficiency caused by the absence or dysfunction of one of NADPH oxidase subunits, with heterogeneous genetic aetiologies. The aim of this study was the CGD patient registry in Greece, the identification of the responsible genotype and the potential correlation with the patient's clinical phenotype. Medical charts of 24 CGD patients, investigated by NBT test or DHR for NADPH oxidase activity, Western blot analysis for NADPH oxidase component expression and DNA sequencing (pyro- and cycle sequencing) for mutation analysis, were reviewed. All patients, but one, were classified into the different types of CGD. Sixteen patients from 14 unrelated families had X-linked CGD (66.7 %), four had mutations in the NCF1 gene (19 %), and three, from two unrelated families, had mutations in NCF2 (9.5 %) [Corrected]. Fifteen mutations were detected in the CYBB gene, including nonsense (53.8 %), splice site (30.8 %) and missense mutations (7.7 %), and deletions (7.7 %). Two novel mutations were identified; one in CYBB and one in NCF1. Carrier detection for X-CGD revealed that the de novo mutation rate was about 7 %. Prenatal diagnosis identified one affected male in three male fetuses tested. In both the X-linked and the autosomal recessive (AR-CGD) group, the gastrointestinal and respiratory manifestations were more common, followed by lympadenopathy in X-CGD and skin infections in the AR-CGD group. The patients with a mutation in CYBB had a wider variability of clinical manifestations and earlier diagnosis (4.6 years) compared to the AR-CGD group (12.9 years). The incidence of CGD in Greece is estimated at 0.90 (95 % CI 0.89-0.91) per 100,000 live births for the last decade. PMID:24081483

  6. Genetics Home Reference: X-linked severe combined immunodeficiency

    MedlinePlus

    ... Genome Research Institute: Learning About Severe Combined Immunodeficiency National Institute of Allergy and Infectious Diseases: Primary Immune ... Manual Consumer Version Orphanet: T-B+ severe ...

  7. Pelvic Inflammatory Disease (PID) Treatment and Care

    MedlinePlus

    ... Herpes Gonorrhea Hepatitis HIV/AIDS & STDs Human Papillomavirus (HPV) Pelvic Inflammatory Disease ... is pelvic inflammatory disease treated? Several types of antibiotics can cure PID. Antibiotic treatment does not, however, reverse any ...

  8. Multivariable PID Controller For Robotic Manipulator

    NASA Technical Reports Server (NTRS)

    Seraji, Homayoun; Tarokh, Mahmoud

    1990-01-01

    Gains updated during operation to cope with changes in characteristics and loads. Conceptual multivariable controller for robotic manipulator includes proportional/derivative (PD) controller in inner feedback loop, and proportional/integral/derivative (PID) controller in outer feedback loop. PD controller places poles of transfer function (in Laplace-transform space) of control system for linearized mathematical model of dynamics of robot. PID controller tracks trajectory and decouples input and output.

  9. Neurodevelopmental Impairment among Infants Born to Mothers Infected with Human Immunodeficiency Virus and Uninfected Mothers from Three Peri-Urban Primary Care Clinics in Harare, Zimbabwe

    ERIC Educational Resources Information Center

    Kandawasvika, Gwendoline Q.; Ogundipe, Enitan; Gumbo, Felicity Z.; Kurewa, Edith N.; Mapingure, Munyaradzi P.; Stray-Pedersen, Babill

    2011-01-01

    Aim: The aim of this article is to document the risk of neurodevelopmental impairment (NDI) among infants enrolled in a programme for the prevention of mother-to-child transmission of HIV (human immunodeficiency virus) in Zimbabwe using the Bayley Infant Neurodevelopmental Screener (BINS). Method: We prospectively followed up infants at three…

  10. Recent advances in transplantation for primary immune deficiency diseases: a comprehensive review.

    PubMed

    de la Morena, M Teresa; Nelson, Robert P

    2014-04-01

    Hematopoietic cell transplantation (HCT) is a curative therapeutic option for severe combined immunodeficiency (SCID), a group of diseases which otherwise carry life expectancies that are of limited duration and quality. Survival following HCT for SCID has improved from approximately 23 to 91 % over the last 40 years. Success with SCID prompted efforts to apply HCT to the therapeutic challenge of well over 20 molecularly defined primary immune deficiency diseases (PID). Such success is due to both early recognition of PIDs and advances in the field of transplantation. Such advances include high-resolution HLA DNA donor-recipient matching, expansion of donor sources, better tolerated conditioning, new antibiotics, and wider availability. International collaborative efforts have provided patients and caregivers information that permit better treatment decisions now, and direct clinicians and investigators to ensure progress in the future. Pioneers in screening for SCID have taken steps to correct the fundamental challenge to successful treatment, which is the rapid discovery and characterization of cases and offering the transplant option to an affected child early in life; blood spot testing for T and B cell receptor quantification is now available to a growing fraction of newborns. Organizations including the Primary Immune Deficiency Treatment Consortium in the USA, The European Society for Primary Immunodeficiency, the European Group for Blood and Marrow Transplantation, the Pediatric Blood and Marrow Transplant Consortium, the United States Immunodeficiency Network, the Immune Deficiency Foundation, and the Jeffrey Modell Foundation are contributing mightily to increase awareness and standardize optimal utilization to the benefit of patients. This review will update the allergist-immunologist concerning disease presentations, indications for transplantation, methodologies, conditioning regimens, and clinical outcomes for patients with PID for which timely HCT is

  11. Gene Therapy for the Treatment of Primary Immune Deficiencies.

    PubMed

    Kuo, Caroline Y; Kohn, Donald B

    2016-05-01

    The use of gene therapy in the treatment of primary immune deficiencies (PID) has advanced significantly in the last decade. Clinical trials for X-linked severe combined immunodeficiency, adenosine deaminase deficiency (ADA), chronic granulomatous disease, and Wiskott-Aldrich syndrome have demonstrated that gene transfer into hematopoietic stem cells and autologous transplant can result in clinical improvement and is curative for many patients. Unfortunately, early clinical trials were complicated by vector-related insertional mutagenic events for several diseases with the exception of ADA-deficiency SCID. These results prompted the current wave of clinical trials for primary immunodeficiency using alternative retro- or lenti-viral vector constructs that are self-inactivating, and they have shown clinical efficacy without leukemic events thus far. The field of gene therapy continues to progress, with improvements in viral vector profiles, stem cell culturing techniques, and site-specific genome editing platforms. The future of gene therapy is promising, and we are quickly moving towards a time when it will be a standard cellular therapy for many forms of PID. PMID:27056559

  12. Common Variable Immunodeficiency.

    PubMed

    Saikia, Biman; Gupta, Sudhir

    2016-04-01

    Common variable immunodeficiency (CVID) is the most common primary immunodeficiency of young adolescents and adults which also affects the children. The disease remains largely under-diagnosed in India and Southeast Asian countries. Although in majority of cases it is sporadic, disease may be inherited in a autosomal recessive pattern and rarely, in autosomal dominant pattern. Patients, in addition to frequent sino-pulmonary infections, are also susceptible to various autoimmune diseases and malignancy, predominantly lymphoma and leukemia. Other characteristic lesions include lymphocytic and granulomatous interstitial lung disease, and nodular lymphoid hyperplasia of gut. Diagnosis requires reduced levels of at least two immunoglobulin isotypes: IgG with IgA and/or IgM and impaired specific antibody response to vaccines. A number of gene mutations have been described in CVID; however, these genetic alterations account for less than 20% of cases of CVID. Flow cytometry aptly demonstrates a disturbed B cell homeostasis with reduced or absent memory B cells and increased CD21(low) B cells and transitional B cell populations. Approximately one-third of patients with CVID also display T cell functional defects. Immunoglobulin therapy remains the mainstay of treatment. Immunologists and other clinicians in India and other South East Asian countries need to be aware of CVID so that early diagnosis can be made, as currently, majority of these patients still go undiagnosed. PMID:26868026

  13. Early Outcomes of Primary Total Hip Arthroplasty for Osteonecrosis of the Femoral Head in Patients with Human Immunodeficiency Virus in China

    PubMed Central

    Zhao, Chang-Song; Li, Xin; Zhang, Qiang; Sun, Sheng; Zhao, Ru-Gang; Cai, Juan

    2015-01-01

    Background: Studies have reported that patients with human immunodeficiency virus (HIV) have a high incidence of osteonecrosis of the femoral head (ONFH). Total hip arthroplasty (THA) is an effective management of ONFH. However, little data exist regarding the use of THA for the HIV patients with ONFH in China. This study reviewed the outcomes of HIV-positive patients who underwent THA for ONFH, compared with HIV-negative individuals. Methods: The patients who underwent THA for ONFH from September 2012 to September 2014 in Beijing Ditan Hospital, Capital Medical University were retrospectively studied. Twenty-eight HIV-positive patients and 35 HIV-negative patients underwent 48 THAs and 45 THAs with cementless components, respectively. Medical records and follow-up data were reviewed. Harris Hip Score (HHS) was applied to evaluate the pain and function of the hips before and after THA. Complications such as wound healing, surgical site infection, deep venous thrombosis, pulmonary embolism, sepsis, mortality, and complications from the prosthesis were reviewed. The operation time, blood loss, and hospital stay were compared between the two groups. Results: The mean follow-up period was 19.5 ± 5.8 months (ranging from 6 to 30 months). The mean age of the HIV-positive patients with osteonecrosis at the time of surgery was 35 years old, which was significantly lower than that of the HIV-negative group (42 years old) (P < 0.05). The HIV-positive patients underwent surgery a mean of 2.5 years after their original symptoms, which was significantly shorter than the HIV-negatives’ (mean 4 years) (P < 0.05). Among HIV-positive patients, the prevalence of being male and rate of bilateral procedures were significantly higher than those in the HIV-negative group (P < 0.05). The operation time in HIV-positive patients was significantly longer than that in HIV-negative patients (P < 0.05). There were no significant differences in blood loss or hospital stay between the two

  14. [Cancer as secondary immunodeficiency. Review].

    PubMed

    Vargas-Camaño, María Eugenia; Guido-Bayardo, Ricardo Leopoldo; Martínez-Aguilar, Nora Ernestina; Castrejón-Vázquez, María Isabel

    2016-01-01

    Secondary immunodeficiencys, previously presented in immunocompetent individuals. The lack of primary or secondary response to the presence of a foreign antigen, in the case of infections is a sentinel data in the diagnosis of immunodeficiency (can be primary or secondary), in the case of a self antigen may generate the presence of Cancer. Cancer has shown an increase in the prevalence and incidence globally. Most current medical treatments in cancer are focused primarily on immunomodulatory actions (immunosuppression / immune stimulation or both). Knowledge of key concepts from the perspective of innate and acquired immunity lead to cancer development, engaging immune surveillance and escape mechanisms of this that contribute to better understand the origin, behavior and treatment of neoplasm's. These treatments can cause immunological disorders such as allergy, anaphylaxis, lack of response immunogenicity care fields specialist in allergy and clinical immunology. PMID:27174760

  15. Genetics Home Reference: hepatic veno-occlusive disease with immunodeficiency

    MedlinePlus

    ... 1 link) National Institute of Allergy and Infectious Diseases: Primary Immune Deficiency Diseases Educational Resources (4 links) Disease InfoSearch: ... Resources (6 links) American Liver Foundation Children's Liver Disease ... Foundation International Patient Organisation for Primary Immunodeficiencies ...

  16. Pelvic Inflammatory Disease (PID) Fact Sheet

    MedlinePlus

    ... a serious condition, in women. 1 in 8 women with a history of PID experience difficulties getting pregnant. You can ... negative STD test results; Using latex condoms the right way every time ... a combination of your medical history, physical exam, and other test results. You may ...

  17. PID techniques: Alternatives to RICH methods

    NASA Astrophysics Data System (ADS)

    Va'vra, J.

    2011-05-01

    In this review article we discuss the recent progress in PID techniques other than the RICH methods. In particular we mention the recent progress in the Transition Radiation Detector (TRD), d E/d x cluster counting, and Time of Flight (TOF) techniques. Invited talk at RICH 2010, May 5, Cassis, France

  18. Identifying the target cell in primary simian immunodeficiency virus (SIV) infection: highly activated memory CD4(+) T cells are rapidly eliminated in early SIV infection in vivo.

    PubMed

    Veazey, R S; Tham, I C; Mansfield, K G; DeMaria, M; Forand, A E; Shvetz, D E; Chalifoux, L V; Sehgal, P K; Lackner, A A

    2000-01-01

    It has recently been shown that rapid and profound CD4(+) T-cell depletion occurs almost exclusively within the intestinal tract of simian immunodeficiency virus (SIV)-infected macaques within days of infection. Here we demonstrate (by three- and four-color flow cytometry) that this depletion is specific to a definable subset of CD4(+) T cells, namely, those having both a highly and/or acutely activated (CD69(+) CD38(+) HLA-DR(+)) and memory (CD45RA(-) Leu8(-)) phenotype. Moreover, we demonstrate that this subset of helper T cells is found primarily within the intestinal lamina propria. Viral tropism for this particular cell type (which has been previously suggested by various studies in vitro) could explain why profound CD4(+) T-cell depletion occurs in the intestine and not in peripheral lymphoid tissues in early SIV infection. Furthermore, we demonstrate that an acute loss of this specific subset of activated memory CD4(+) T cells may also be detected in peripheral blood and lymph nodes in early SIV infection. However, since this particular cell type is present in such small numbers in circulation, its loss does not significantly affect total CD4(+) T cell counts. This finding suggests that SIV and, presumably, human immunodeficiency virus specifically infect, replicate in, and eliminate definable subsets of CD4(+) T cells in vivo. PMID:10590091

  19. Variable-order fuzzy fractional PID controller.

    PubMed

    Liu, Lu; Pan, Feng; Xue, Dingyu

    2015-03-01

    In this paper, a new tuning method of variable-order fractional fuzzy PID controller (VOFFLC) is proposed for a class of fractional-order and integer-order control plants. Fuzzy logic control (FLC) could easily deal with parameter variations of control system, but the fractional-order parameters are unable to change through this way and it has confined the effectiveness of FLC. Therefore, an attempt is made in this paper to allow all the five parameters of fractional-order PID controller vary along with the transformation of system structure as the outputs of FLC, and the influence of fractional orders λ and μ on control systems has been investigated to make the fuzzy rules for VOFFLC. Four simulation results of different plants are shown to verify the availability of the proposed control strategy. PMID:25440947

  20. PID Control Effectiveness for Surface Reactor Concepts

    SciTech Connect

    Dixon, David D.; Marsh, Christopher L.; Poston, David I.

    2007-01-30

    Control of space and surface fission reactors should be kept as simple as possible, because of the need for high reliability and the difficulty to diagnose and adapt to control system failures. Fortunately, compact, fast-spectrum, externally controlled reactors are very simple in operation. In fact, for some applications it may be possible to design low-power surface reactors without the need for any reactor control after startup; however, a simple proportional, integral, derivative (PID) controller can allow a higher performance concept and add more flexibility to system operation. This paper investigates the effectiveness of a PID control scheme for several anticipated transients that a surface reactor might experience. To perform these analyses, the surface reactor transient code FRINK was modified to simulate control drum movements based on bulk coolant temperature.

  1. Quantum Efficiency Loss after PID Stress: Wavelength Dependence on Cell Surface and Cell Edge

    SciTech Connect

    Oh, Jaewon; Bowden, Stuart; TamizhMani, GovindaSamy; Hacke, Peter

    2015-06-14

    It is known that the potential induced degradation (PID) stress of conventional p-base solar cells affects power, shunt resistance, junction recombination, and quantum efficiency (QE). One of the primary solutions to address the PID issue is a modification of chemical and physical properties of antireflection coating (ARC) on the cell surface. Depending on the edge isolation method used during cell processing, the ARC layer near the edges may be uniformly or non-uniformly damaged. Therefore, the pathway for sodium migration from glass to the cell junction could be either through all of the ARC surface if surface and edge ARC have low quality or through the cell edge if surface ARC has high quality but edge ARC is defective due to certain edge isolation process. In this study, two PID susceptible cells from two different manufacturers have been investigated. The QE measurements of these cells before and after PID stress were performed at both surface and edge. We observed the wavelength dependent QE loss only in the first manufacturer's cell but not in the second manufacturer's cell. The first manufacturer's cell appeared to have low quality ARC whereas the second manufacturer's cell appeared to have high quality ARC with defective edge. To rapidly screen a large number of cells for PID stress testing, a new but simple test setup that does not require laminated cell coupon has been developed and is used in this investigation.

  2. Nef Stimulates Human Immunodeficiency Virus Type 1 Replication in Primary T Cells by Enhancing Virion-Associated gp120 Levels: Coreceptor-Dependent Requirement for Nef in Viral Replication†

    PubMed Central

    Lundquist, Christopher A.; Zhou, Jing; Aiken, Christopher

    2004-01-01

    The Nef protein enhances human immunodeficiency virus type 1 (HIV-1) replication through an unknown mechanism. We and others have previously reported that efficient HIV-1 replication in activated primary CD4+ T cells depends on the ability of Nef to downregulate CD4 from the cell surface. Here we demonstrate that Nef greatly enhances the infectivity of HIV-1 particles produced in primary T cells. Nef-defective HIV-1 particles contained significantly reduced quantities of gp120 on their surface; however, Nef did not affect the levels of virion-associated gp41, indicating that Nef indirectly stabilizes the association of gp120 with gp41. Surprisingly, Nef was not required for efficient replication of viruses that use CCR5 for entry, nor did Nef influence the infectivity or gp120 content of these virions. Nef also inhibited the incorporation of CD4 into HIV-1 particles released from primary T cells. We propose that Nef, by downregulating cell surface CD4, enhances HIV-1 replication by inhibiting CD4-induced dissociation of gp120 from gp41. The preferential requirement for Nef in the replication of X4-tropic HIV-1 suggests that the ability of Nef to downregulate CD4 may be most important at later stages of disease when X4-tropic viruses emerge. PMID:15163722

  3. [Common variable immunodeficiency: a clinical challenge].

    PubMed

    Warnatz, K; Goldacker, S

    2013-09-01

    Common variable immunodeficiency (CVID) represents the most common clinically relevant form of primary immunodeficiency. This heterogeneous antibody deficiency syndrome is characterized not only by susceptibility to bacterial respiratory tract infections but displays additional signs of immune dysregulation, such as autoimmunity, chronic inflammation and lymphoproliferation in more than 30 % of the patients. Due to poor awareness the diagnosis is often delayed by 4-6 years. A close collaboration in patient care with a center specialized in primary immunodeficiency is recommended. Regular follow-up visits include assessment of adequate immunoglobulin replacement therapy and screening for manifestation of secondary complications. Regular substitution with intravenous or subcutaneous immunoglobulins has more or less normalized life expectancy of patients with isolated susceptibility to bacterial infections. Therefore, the current core task in the management of CVID patients is the elaboration of more effective and safer forms of prophylaxis and treatment of sequelae of immune dysregulation in the lungs, intestines and liver of affected patients. PMID:23929240

  4. Primary extranodal non-hodgkin lymphoma of the head and neck in patients with acquired immunodeficiency syndrome: a clinicopathologic study of 24 patients in a single hospital of infectious diseases in Argentina.

    PubMed

    Corti, Marcelo; Villafañe, María; Bistmans, Alicia; Narbaitz, Marina; Gilardi, Leonardo

    2014-07-01

    Introduction Extranodal non-Hodgkin lymphomas (NHLs) are commonly described in patients with acquired immunodeficiency syndrome (AIDS) and are related with an atypical morphology and aggressive clinical course. AIDS-associated lymphomas are characterized by their rapid progression, frequent extranodal manifestations, and poor outcome. Objective The aim of this article is to remake the clinical features of head and neck (HN) NHL in patients with AIDS to facilitate early diagnosis and treatment. Methods We evaluated the epidemiologic, clinical, immunologic, virologic, and histopathologic characteristics of 24 patients with human immunodeficiency virus (HIV)/AIDS with primary HN NHL treated at a single institution between 2002 and 2012. Histopathologic diagnosis was made according to the criteria of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. Additional immunohistochemical stains were applied in all cases. Results Eighteen patients (75%) were men and the median of age was 39 years. The gingiva and the hard palate were the most common sites of the lesions (15 patients, 62.5%). Lactate dehydrogenase levels were elevated in 16 cases (84%). Bone marrow infiltration was detected only in 4 cases (16.6%). The median CD4 T-cell count was 100 cells/µL. According to the histopathologic evaluation, the most common subtype was diffuse large B-cell lymphoma (12 cases, 50%), followed by plasmablastic lymphoma (9 cases, 37.5%) and Burkitt lymphoma (3 cases, 12.5%). Conclusion HN NHL is a severe complication of advanced HIV/AIDS disease. Early diagnosis followed by chemotherapy plus highly active antiretroviral treatment is necessary to improve the prognosis and the survival of these patients. PMID:25992103

  5. Primary Extranodal Non-Hodgkin Lymphoma of the Head and Neck in Patients with Acquired Immunodeficiency Syndrome: A Clinicopathologic Study of 24 Patients in a Single Hospital of Infectious Diseases in Argentina

    PubMed Central

    Corti, Marcelo; Villafañe, María; Bistmans, Alicia; Narbaitz, Marina; Gilardi, Leonardo

    2014-01-01

    Introduction Extranodal non-Hodgkin lymphomas (NHLs) are commonly described in patients with acquired immunodeficiency syndrome (AIDS) and are related with an atypical morphology and aggressive clinical course. AIDS-associated lymphomas are characterized by their rapid progression, frequent extranodal manifestations, and poor outcome. Objective The aim of this article is to remake the clinical features of head and neck (HN) NHL in patients with AIDS to facilitate early diagnosis and treatment. Methods We evaluated the epidemiologic, clinical, immunologic, virologic, and histopathologic characteristics of 24 patients with human immunodeficiency virus (HIV)/AIDS with primary HN NHL treated at a single institution between 2002 and 2012. Histopathologic diagnosis was made according to the criteria of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. Additional immunohistochemical stains were applied in all cases. Results Eighteen patients (75%) were men and the median of age was 39 years. The gingiva and the hard palate were the most common sites of the lesions (15 patients, 62.5%). Lactate dehydrogenase levels were elevated in 16 cases (84%). Bone marrow infiltration was detected only in 4 cases (16.6%). The median CD4 T-cell count was 100 cells/µL. According to the histopathologic evaluation, the most common subtype was diffuse large B-cell lymphoma (12 cases, 50%), followed by plasmablastic lymphoma (9 cases, 37.5%) and Burkitt lymphoma (3 cases, 12.5%). Conclusion HN NHL is a severe complication of advanced HIV/AIDS disease. Early diagnosis followed by chemotherapy plus highly active antiretroviral treatment is necessary to improve the prognosis and the survival of these patients. PMID:25992103

  6. A human primary T-lymphocyte-derived human immunodeficiency virus type 1 Tat-associated kinase phosphorylates the C-terminal domain of RNA polymerase II and induces CAK activity.

    PubMed

    Nekhai, S; Shukla, R R; Kumar, A

    1997-10-01

    Tat protein mediates transactivation of human immunodeficiency virus type 1 (HIV-1), which results in more-efficient transcript elongation. Since phosphorylation of C-terminal domain (CTD) of RNA polymerase II correlates with its enhanced processivity, we studied the properties of a Tat-associated CTD kinase derived from mitogenically stimulated human primary T lymphocytes (TTK). TTK binds to full-length Tat and specifically phosphorylates CTD and CDK2. This dual kinase activity is characteristic of CDK-activating kinase (CAK). The CTD kinase activity is induced upon mitogenic stimulation of primary T lymphocytes. Fractionation of T-cell lysate demonstrates that Tat-associated CTD kinase activity elutes in two peaks. About 60% of Tat-associated CTD kinase copurifies with CDK2 kinase activity and contains the CAK components CDK7 and cyclin H. The rest of Tat-associated kinase is free of CDK2 kinase activity and the CAK components and thus may represent a novel CTD kinase. The kinase activities of TTK are blocked by the adenosine analog 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB) as well as by the kinase inhibitor H8 at concentrations known to block transcript elongation. Importantly, the Tat-associated kinase markedly induced CAK. We suggest that the mechanism of Tat-mediated processive transcription of the HIV-1 promoter includes a Tat-associated CAK activator. PMID:9311822

  7. Infection of Macrophages and Dendritic Cells with Primary R5-Tropic Human Immunodeficiency Virus Type 1 Inhibited by Natural Polyreactive Anti-CCR5 Antibodies Purified from Cervicovaginal Secretions▿

    PubMed Central

    Eslahpazir, Jobin; Jenabian, Mohammad-Ali; Bouhlal, Hicham; Hocini, Hakim; Carbonneil, Cédric; Grésenguet, Gérard; Kéou, François-Xavier Mbopi; LeGoff, Jérôme; Saïdi, Héla; Requena, Mary; Nasreddine, Nadine; de Dieu Longo, Jean; Kaveri, Srinivas V.; Bélec, Laurent

    2008-01-01

    Heterosexual contact is the primary mode of human immunodeficiency virus (HIV) type 1 (HIV-1) transmission worldwide. The chemokine receptor CCR5 is the major coreceptor that is associated with the mucosal transmission of R5-tropic HIV-1 during sexual intercourse. The CCR5 molecule is thus a target for antibody-based therapeutic strategies aimed at blocking HIV-1 entry into cells. We have previously demonstrated that polyreactive natural antibodies (NAbs) from therapeutic preparations of immunoglobulin G and from human breast milk contain NAbs directed against CCR5. Such antibodies inhibit the infection of human macrophages and T lymphocytes by R5-tropic isolates of HIV in vitro. In the present study, we demonstrate that human immunoglobulins from the cervicovaginal secretions of HIV-seronegative or HIV-seropositive women contain NAbs directed against the HIV-1 coreceptor CCR5. Natural affinity-purified anti-CCR5 antibodies bound to CCR5 expressed on macrophages and dendritic cells and further inhibited the infection of macrophages and dendritic cells with primary and laboratory-adapted R5-tropic HIV but not with X4-tropic HIV. Natural anti-CCR5 antibodies moderately inhibited R5-tropic HIV transfer from monocyte-derived dendritic cells to autologous T cells. Our results suggest that mucosal anti-CCR5 antibodies from healthy immunocompetent donors may hamper the penetration of HIV and may be suitable for use in the development of novel passive immunotherapy regimens in specific clinical settings of HIV infection. PMID:18353923

  8. Proteomic analyses of monocyte-derived macrophages infected with human immunodeficiency virus type 1 primary isolates from Hispanic women with and without cognitive impairment

    PubMed Central

    Toro-Nieves, DM; Rodriguez, Y; Plaud, M; Ciborowski, P; Duan, F; Laspiur, J Pérez; Wojna, V; Meléndez, LM

    2009-01-01

    The signature for human immunodeficiency virus type 1 (HIV-1) neurovirulence remains a subject of intense debate. Macrophage viral tropism is one prerequisite but others, including virus-induced alterations in innate and adaptive immunity, remain under investigation. HIV-1–infected mononuclear phagocytes (MPs; perivascular macrophages and microglia) secrete toxins that affect neurons. The authors hypothesize that neurovirulent HIV-1 variants affect the MP proteome by inducing a signature of neurotoxic proteins and thus affect cognitive function. To test this hypothesis, HIV-1 isolates obtained from peripheral blood of women with normal cognition (NC) were compared to isolates obtained from women with cognitive impairment (CI) and to the laboratory adapted SF162, a spinal fluid R5 isolate from a patient with HIV-1–associated dementia. HIV-1 isolates were used to infect monocyte-derived macrophages (MDMs) and infection monitored by secreted HIV-1 p24 by enzyme-linked immunosorbent assay (ELISA). Cell lysates of uninfected and HIV-1–infected MDMs at 14 days post infection were fractionated by cationic exchange chromatography and analyzed by surface enhanced laser desorption ionization time of flight (SELDI-TOF) using generalized estimating equations statistics. Proteins were separated by one-dimensional sodium dodecyl sulfate–polyacrylamide gel electrophoresis (1D SDS-PAGE) and identified by tandem mass spectrometry. Levels of viral replication were similar amongst the HIV-1 isolates, although higher levels were obtained from one viral strain obtained from a patient with CI. Significant differences were found in protein profiles between virus-infected MDMs with NC, CI, and SF162 isolates (adjusted P value after multiple testing corrections, or q value < .10). The authors identified 6 unique proteins in NC, 7 in SF162, and 20 in CI. Three proteins were common to SF162 and CI strains. The MDM proteins linked to infection with CI strains were related to apoptosis

  9. Soft Real-Time PID Control on a VME Computer

    NASA Technical Reports Server (NTRS)

    Karayan, Vahag; Sander, Stanley; Cageao, Richard

    2007-01-01

    microPID (uPID) is a computer program for real-time proportional + integral + derivative (PID) control of a translation stage in a Fourier-transform ultraviolet spectrometer. microPID implements a PID control loop over a position profile at sampling rate of 8 kHz (sampling period 125microseconds). The software runs in a strippeddown Linux operating system on a VersaModule Eurocard (VME) computer operating in real-time priority queue using an embedded controller, a 16-bit digital-to-analog converter (D/A) board, and a laser-positioning board (LPB). microPID consists of three main parts: (1) VME device-driver routines, (2) software that administers a custom protocol for serial communication with a control computer, and (3) a loop section that obtains the current position from an LPB-driver routine, calculates the ideal position from the profile, and calculates a new voltage command by use of an embedded PID routine all within each sampling period. The voltage command is sent to the D/A board to control the stage. microPID uses special kernel headers to obtain microsecond timing resolution. Inasmuch as microPID implements a single-threaded process and all other processes are disabled, the Linux operating system acts as a soft real-time system.

  10. [HOW TO APPROACH A PATIENT WITH SUSPECTED IMMUNODEFICIENCY].

    PubMed

    Toker, Ori; Aggmon-Levin, Nancy; Somech, Raz

    2016-03-01

    Our immune system protects us from various pathogens, autoimmune processes and malignancy. Primary immunodeficiency disorders are rare, however in contrast to the conventional perception, primary immunodeficiency diseases are more common than expected and may occur at any age. An insult to the immune system, primary or secondary, may lead to an increased incidence of infectious diseases, autoimmune diseases and malignancies. Primary care physicians, frequently encounter children and adults who suffer from recurrent infections, emphasizing the need for a structured approach for the evaluation of patients with suspected immunodeficiency. The growing knowledge of the fundamental mechanisms and function of the immune system together with recent developments in the field of clinical immunodeficiency enables us to use advanced diagnostic tools for the early diagnosis and treatment of these patients. In this review, we summarize the main aspects and updates of primary and secondary immune deficiency diseases, outline the "red flags" of immunodeficiency states and offer a stepwise workup approach for primary physicians and clinical immunology specialists. Some of the immunodeficiency "red flags" include recurrent infections, invasive infections, atypical pathogens, partial response to antibiotic treatment and frequent use of antibiotics, failure to thrive, chronic diarrhea and fungal infections, unexplained skin rash and a family history. PMID:27305752

  11. PID techniques: Alternatives to RICH Methods

    SciTech Connect

    Vavra, J.; /SLAC

    2011-03-01

    In this review article we discuss the recent progress in PID techniques other than the RICH methods. In particular we mention the recent progress in the Transition Radiation Detector (TRD), dE/dx cluster counting, and Time Of Flight (TOF) techniques. The TRD technique is mature and has been tried in many hadron colliders. It needs space though, about 20cm of detector radial space for every factor of 10 in the {pi}/e rejection power, and this tends to make such detectors large. Although the cluster counting technique is an old idea, it was never tried in a real physics experiment. Recently, there are efforts to revive it for the SuperB experiment using He-based gases and waveform digitizing electronics. A factor of almost 2 improvement, compared to the classical dE/dx performance, is possible in principle. However, the complexity of the data analysis will be substantial. The TOF technique is well established, but introduction of new fast MCP-PMT and G-APD detectors creates new possibilities. It seems that resolutions below 20-30ps may be possible at some point in the future with relatively small systems, and perhaps this could be pushed down to 10-15ps with very small systems, assuming that one can solve many systematic issues. However, the cost, rate limitation, aging and cross-talk in multi-anode devices at high BW are problems. There are several groups working on these issues, so progress is likely. Table 6 summarizes the author's opinion of pros and cons of various detectors presented in this paper based on their operational capabilities. We refer the reader to Ref.40 for discussion of other more general limits from the PID point of view.

  12. The Effect of Latency Reversal Agents on Primary CD8+ T Cells: Implications for Shock and Kill Strategies for Human Immunodeficiency Virus Eradication.

    PubMed

    Walker-Sperling, Victoria E; Pohlmeyer, Christopher W; Tarwater, Patrick M; Blankson, Joel N

    2016-06-01

    Shock and kill strategies involving the use of small molecules to induce viral transcription in resting CD4+ T cells (shock) followed by immune mediated clearance of the reactivated cells (kill), have been proposed as a method of eliminating latently infected CD4+ T cells. The combination of the histone deacetylase (HDAC) inhibitor romidepsin and protein kinase C (PKC) agonist bryostatin-1 is very effective at reversing latency in vitro. However, we found that primary HIV-1 specific CD8+ T cells were not able to eliminate autologous resting CD4+ T cells that had been reactivated with these drugs. We tested the hypothesis that the drugs affected primary CD8+ T cell function and found that both agents had inhibitory effects on the suppressive capacity of HIV-specific CD8+ T cells from patients who control viral replication without antiretroviral therapy (elite suppressors/controllers). The inhibitory effect was additive and multi-factorial in nature. These inhibitory effects were not seen with prostratin, another PKC agonist, either alone or in combination with JQ1, a bromodomain-containing protein 4 inhibitor. Our results suggest that because of their adverse effects on primary CD8+ T cells, some LRAs may cause immune-suppression and therefore should be used with caution in shock and kill strategies. PMID:27428432

  13. A tuning method of two degrees of freedom PID controller

    SciTech Connect

    Kasahara, Masato; Kimbara, Akiomi; Kurosu, Shigeru; Matsuba, Tadahiko; Kamimura, Kazuyuki; Murasawa, Itaru; Hashimoto, Yukihiro

    1997-12-31

    This paper proposes a new tuning method when using a two degrees of freedom proportional-integral-derivative (PID) controller. Its control performance for a first-order lag plus deadtime system is shown as an example of the commonly approximated controlled plants in the heating, ventilating, and air-conditioning (HVAC) field. Reference and disturbance input changes to a conventional PID controller do not necessarily give a satisfactory response. To overcome this problem, several two degrees of freedom PID (2 DOF PID) algorithms have been developed to replace the conventional PID controllers. However, when these techniques are applied to real plants, it is not usually easy to obtain a set of optimum tuning parameters. To evaluate the control performance, a comparison is carried out between the two tuning methods--the optimization technique and the partial model matching method--using simulation. Graphs by which the controller parameters can be related to dynamics of a popular plant are developed. The 2 DOF PID control is studied taking into account modeling error due to a change in plant characteristics. It is found that the 2 DOF PID controller designed based on the partial model matching method is robust and useful in simulations where a traditional PID controller would be used.

  14. Emergence of clusters of CRF02_AG and B human immunodeficiency viral strains among men having sex with men exhibiting HIV primary infection in southeastern France.

    PubMed

    Tamalet, Catherine; Ravaux, Isabelle; Moreau, Jacques; Brégigeon, Sylvie; Tourres, Christian; Richet, Hervé; Abat, Cedric; Colson, Philippe

    2015-08-01

    The number of new HIV diagnoses is increasing in the western world and transmission clusters have been recently identified among men having sex with men despite Highly Active Antiretroviral Therapy efficacy. The objective of this study was to assess temporal trends, epidemiological, clinical and virological characteristics of primary HIV infections. A retrospective analysis of 79 patients presenting primary HIV infections from 2005 to 2012 was performed in Marseille University Hospitals, southeastern France. Clinical, epidemiological and immunovirological data including phylogeny based on the polymerase gene were collected. 65 males and 14 females were enrolled. The main transmission route was homosexual contact (60.8%). Patients were mostly infected with subtype B (73.4%) and CRF02_AG (21.5%) HIV-1 strains. An increase in the annual number of HIV seroconversions among new HIV diagnoses from 5% in 2005 to 11.2% in 2012 (P = 0.06) and of the proportion of CRF02_AG HIV strains among primary HIV infections in 2011-2012 as compared to 2005-2010 (P = 0.055) was observed. Phylogenetic analysis revealed four transmission clusters including three transmission clusters among men having sex with men: two large clusters of nine CRF02_AG, six B HIV strains; and one small cluster of three B HIV strains. Clusters involved more frequently men (P = 0.01) belonging to caucasian ethicity (P = 0.05), with a higher HIV RNA load at inclusion (P = 0.03). These data highlight the importance of improving epidemiological surveillance and of implementing suitable prevention strategies to control the spread of HIV transmission among men having sex with men. PMID:25873310

  15. Testing for Human Immunodeficiency Virus

    MedlinePlus

    ... incisions made in the mother’s abdomen and uterus. Human Immunodeficiency Virus (HIV): A virus that attacks certain cells of the body’s immune system and causes acquired immunodeficiency syndrome (AIDS). Immune System: ...

  16. Cytokine influence on simian immunodeficiency virus replication within primary macrophages. TNF-alpha, but not GMCSF, enhances viral replication on a per-cell basis.

    PubMed Central

    Walsh, D. G.; Horvath, C. J.; Hansen-Moosa, A.; MacKey, J. J.; Sehgal, P. K.; Daniel, M. D.; Desrosiers, R. C.; Ringler, D. J.

    1991-01-01

    The control of HIV-1 or SIV replication within macrophages is probably influenced by a variety of viral and cellular factors. Of the cellular factors, the authors have studied cytokine influence on SIV replication in vitro utilizing simian alveolar macrophages and uncloned SIVmacMTV, a macrophage-tropic variant. The approach allowed quantification of viral replication on a per-cell basis. As reported for HIV-1 replication in macrophages, TNF-alpha significantly increased SIV production in these macrophage cultures. GMCSF also resulted in marked increases in SIV gag protein in culture supernatants. However, after correcting for differences in total cell numbers and numbers of gag-containing cells in the treated and untreated cultures, GMCSF did not upregulate SIV production on a per-cell basis. IL-6 increased SIV replication little if at all but induced significantly greater cytopathic changes in the treated cultures compared with infected, untreated cultures. In contrast, IFN-gamma greatly decreased replication. Our results for GMCSF, IFN-gamma, and IL-6 are in contrast to previously published reports of cytokine control of HIV-1 growth in target cells, and they stress the importance of cell number analyses and the use of primary cultures in the study of lentiviral replication kinetics in macrophages. Images Figure 5 PMID:1928304

  17. A new adaptive configuration of PID type fuzzy logic controller.

    PubMed

    Fereidouni, Alireza; Masoum, Mohammad A S; Moghbel, Moayed

    2015-05-01

    In this paper, an adaptive configuration for PID type fuzzy logic controller (FLC) is proposed to improve the performances of both conventional PID (C-PID) controller and conventional PID type FLC (C-PID-FLC). The proposed configuration is called adaptive because its output scaling factors (SFs) are dynamically tuned while the controller is functioning. The initial values of SFs are calculated based on its well-tuned counterpart while the proceeding values are generated using a proposed stochastic hybrid bacterial foraging particle swarm optimization (h-BF-PSO) algorithm. The performance of the proposed configuration is evaluated through extensive simulations for different operating conditions (changes in reference, load disturbance and noise signals). The results reveal that the proposed scheme performs significantly better over the C-PID controller and the C-PID-FLC in terms of several performance indices (integral absolute error (IAE), integral-of-time-multiplied absolute error (ITAE) and integral-of-time-multiplied squared error (ITSE)), overshoot and settling time for plants with and without dead time. PMID:25530256

  18. A comparison of fuzzy logic-PID control strategies for PWR pressurizer control

    SciTech Connect

    Kavaklioglu, K.; Ikonomopoulos, A. )

    1993-01-01

    This paper describes the results obtained from a comparison performed between classical proportional-integral-derivative (PID) and fuzzy logic (FL) controlling the pressure in a pressurized water reactor (PWR). The two methodologies have been tested under various transient scenarios, and their performances are evaluated with respect to robustness and on-time response to external stimuli. One of the main concerns in the safe operation of PWR is the pressure control in the primary side of the system. In order to maintain the pressure in a PWR at the desired level, the pressurizer component equipped with sprayers, heaters, and safety relief valves is used. The control strategy in a Westinghouse PWR is implemented with a PID controller that initiates either the electric heaters or the sprayers, depending on the direction of the coolant pressure deviation from the setpoint.

  19. IMC-EB10, an anti-FLT3 monoclonal antibody, prolongs survival and reduces nonobese diabetic/severe combined immunodeficient engraftment of some acute lymphoblastic leukemia cell lines and primary leukemic samples.

    PubMed

    Piloto, Obdulio; Nguyen, Bao; Huso, David; Kim, Kyu-Tae; Li, Yiwen; Witte, Larry; Hicklin, Daniel J; Brown, Patrick; Small, Donald

    2006-05-01

    The class III receptor tyrosine kinase FLT3 is expressed on the blasts of >90% of patients with B-lineage acute lymphoblastic leukemias (ALL). In addition, it is expressed at extremely high levels in ALL patients with mixed lineage leukemia rearrangements or hyperdiploidy and is sometimes mutated in these same patients. In this report, we investigate the effects of treating ALL cell lines and primary samples with human anti-FLT3 monoclonal antibodies (mAb) capable of preventing binding of FLT3 ligand. In vitro studies, examining the ability of two anti-FLT3 mAbs (IMC-EB10 and IMC-NC7) to affect FLT3 activation and downstream signaling in ALL cell lines and primary blasts, yielded variable results. FLT3 phosphorylation was consistently inhibited by IMC-NC7 treatment, but in some cell lines, IMC-EB10 actually stimulated FLT3 activation, possibly as a result of antibody-mediated receptor dimerization. Through antibody-dependent, cell-mediated cytotoxicity, such an antibody could still prove efficacious against leukemia cells in vivo. In fact, IMC-EB10 treatment significantly prolonged survival and/or reduced engraftment of several ALL cell lines and primary ALL samples in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This occurred even when IMC-EB10 treatment resulted in FLT3 activation in vitro. Moreover, fluorescence-activated cell sorting and PCR analysis of IMC-EB10-treated NOD/SCID mice surviving 150 days post-leukemic cell injection revealed that FLT3 immunotherapy reduced leukemic engraftment below the level of detection in these assays (<0.001%). Furthermore, in vivo IMC-EB10 treatment did not select for resistant cells, because cells surviving IMC-EB10 treatment remain sensitive to IMC-EB10 cytotoxicity upon retransplantation. In vivo studies involving either partial depletion or activation of natural killer (NK) cells show that most of the cytotoxic effect of IMC-EB10 is mediated through NK cells. Therefore, such an antibody, either

  20. Turbine speed control system based on a fuzzy-PID

    NASA Astrophysics Data System (ADS)

    Sun, Jian-Hua; Wang, Wei; Yu, Hai-Yan

    2008-12-01

    The flexibility demand of marine nuclear power plant is very high, the multiple parameters of the marine nuclear power plant with the once-through steam generator are strongly coupled, and the normal PID control of the turbine speed can’t meet the control demand. This paper introduces a turbine speed Fuzzy-PID controller to coordinately control the steam pressure and thus realize the demand for quick tracking and steady state control over the turbine speed by using the Fuzzy control’s quick dynamic response and PID control’s steady state performance. The simulation shows the improvement of the response time and steady state performance of the control system.

  1. Human Immunodeficiency Virus-Specific Gamma Interferon Enzyme-Linked Immunospot Assay Responses Targeting Specific Regions of the Proteome during Primary Subtype C Infection Are Poor Predictors of the Course of Viremia and Set Point▿

    PubMed Central

    Gray, Clive M.; Mlotshwa, Mandla; Riou, Catherine; Mathebula, Tiyani; de Assis Rosa, Debra; Mashishi, Tumelo; Seoighe, Cathal; Ngandu, Nobubelo; van Loggerenberg, Francois; Morris, Lynn; Mlisana, Koleka; Williamson, Carolyn; Karim, Salim Abdool

    2009-01-01

    It is unknown whether patterns of human immunodeficiency virus (HIV)-specific T-cell responses during acute infection may influence the viral set point and the course of disease. We wished to establish whether the magnitude and breadth of HIV type 1 (HIV-1)-specific T-cell responses at 3 months postinfection were correlated with the viral-load set point at 12 months and hypothesized that the magnitude and breadth of HIV-specific T-cell responses during primary infection would predict the set point. Gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses across the complete proteome were measured in 47 subtype C HIV-1-infected participants at a median of 12 weeks postinfection. When corrected for amino acid length and individuals responding to each region, the order of recognition was as follows: Nef > Gag > Pol > Rev > Vpr > Env > Vpu > Vif > Tat. Nef responses were significantly (P < 0.05) dominant, targeted six epitopic regions, and were unrelated to the course of viremia. There was no significant difference in the magnitude and breadth of responses for each protein region with disease progression, although there was a trend of increased breadth (mean, four to seven pools) in rapid progressors. Correlation of the magnitude and breadth of IFN-γ responses with the viral set point at 12 months revealed almost zero association for each protein region. Taken together, these data demonstrate that the magnitude and breadth of IFN-γ ELISPOT assay responses at 3 months postinfection are unrelated to the course of disease in the first year of infection and are not associated with, and have low predictive power for, the viral set point at 12 months. PMID:18945774

  2. Protein Microarrays: A New Tool for the Study of Autoantibodies in Immunodeficiency

    PubMed Central

    Rosenberg, Jacob M.; Utz, Paul J.

    2015-01-01

    Autoimmunity is highly coincident with immunodeficiency. In a small but growing number of primary immunodeficiencies, autoantibodies are diagnostic of a given disease and implicated in disease pathogenesis. In order to improve our understanding of the role of autoantibodies in immunodeficiencies and to discover novel autoantibodies, new proteomic tools are needed. Protein microarrays have the ability to screen for reactivity to hundreds to many thousands of unique autoantigens simultaneously on a single chip using minimal serum input. Here, we review different types of protein microarrays and how they can be useful in framing the study of primary and secondary immunodeficiencies. PMID:25904912

  3. Protein microarrays: a new tool for the study of autoantibodies in immunodeficiency.

    PubMed

    Rosenberg, Jacob M; Utz, Paul J

    2015-01-01

    Autoimmunity is highly coincident with immunodeficiency. In a small but growing number of primary immunodeficiencies, autoantibodies are diagnostic of a given disease and implicated in disease pathogenesis. In order to improve our understanding of the role of autoantibodies in immunodeficiencies and to discover novel autoantibodies, new proteomic tools are needed. Protein microarrays have the ability to screen for reactivity to hundreds to many thousands of unique autoantigens simultaneously on a single chip using minimal serum input. Here, we review different types of protein microarrays and how they can be useful in framing the study of primary and secondary immunodeficiencies. PMID:25904912

  4. Acquired immunodeficiency syndrome: neuroradiologic findings.

    PubMed

    Kelly, W M; Brant-Zawadzki, M

    1983-11-01

    Central nervous system complications depicted by CT in ten patients with acquired immunodeficiency syndrome are described. Three patients had multifocal intra-axial enhancing lesions representing atypical brain abscesses (two with toxoplasmosis, one with candidiasis). A fourth patient with multifocal "ring" lesions whose biopsy was interpreted as suggestive of toxoplasmosis responded poorly to treatment. Following his death three months later of Pneumocystis carinii pneumonia, autopsy revealed primary intracerebral immunoblastic lymphoma. One patient had Kaposi sarcoma involving the right frontal lobe (seen as an enhancing mass on the CT scan). CT findings in the remaining five patients revealed mild to moderate enlargement of cerebrospinal fluid spaces (including ventricles and basal cisternae) as a result of cryptococcal meningitis in three patients and "aseptic" meningitis in two. The two patients in whom early biopsy confirmed toxoplasmosis responded well to anti-infective therapy, resulting in dramatic clinical recoveries. PMID:6622693

  5. Toll-like receptor signaling in primary immune deficiencies.

    PubMed

    Maglione, Paul J; Simchoni, Noa; Cunningham-Rundles, Charlotte

    2015-11-01

    Toll-like receptors (TLRs) recognize common microbial or host-derived macromolecules and have important roles in early activation of the immune system. Patients with primary immune deficiencies (PIDs) affecting TLR signaling can elucidate the importance of these proteins to the human immune system. Defects in interleukin-1 receptor-associated kinase-4 and myeloid differentiation factor 88 (MyD88) lead to susceptibility to infections with bacteria, while mutations in nuclear factor-κB essential modulator (NEMO) and other downstream mediators generally induce broader susceptibility to bacteria, viruses, and fungi. In contrast, TLR3 signaling defects are specific for susceptibility to herpes simplex virus type 1 encephalitis. Other PIDs induce functional alterations of TLR signaling pathways, such as common variable immunodeficiency in which plasmacytoid dendritic cell defects enhance defective responses of B cells to shared TLR agonists. Dampening of TLR responses is seen for TLRs 2 and 4 in chronic granulomatous disease (CGD) and X-linked agammaglobulinemia (XLA). Enhanced TLR responses, meanwhile, are seen for TLRs 5 and 9 in CGD, TLRs 4, 7/8, and 9 in XLA, TLRs 2 and 4 in hyper IgE syndrome, and for most TLRs in adenosine deaminase deficiency. PMID:25930993

  6. Familial hepatopulmonary syndrome in common variable immunodeficiency.

    PubMed

    Holmes, S N; Condliffe, A; Griffiths, W; Baxendale, H; Kumararatne, D S

    2015-04-01

    Common Variable Immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies which lead to a range of complications, including infectious, neoplastic and inflammatory disorders. This report describes monozygotic twin brothers with CVID who developed cryptogenic liver disease and subsequently hepatopulmonary syndrome (HPS). This is the second report of the association of HPS and CVID. Its occurrence in two identical twins implicates a genetic basis. PMID:25708586

  7. Design of PID-type controllers using multiobjective genetic algorithms.

    PubMed

    Herreros, Alberto; Baeyens, Enrique; Perán, José R

    2002-10-01

    The design of a PID controller is a multiobjective problem. A plant and a set of specifications to be satisfied are given. The designer has to adjust the parameters of the PID controller such that the feedback interconnection of the plant and the controller satisfies the specifications. These specifications are usually competitive and any acceptable solution requires a tradeoff among them. An approach for adjusting the parameters of a PID controller based on multiobjective optimization and genetic algorithms is presented in this paper. The MRCD (multiobjective robust control design) genetic algorithm has been employed. The approach can be easily generalized to design multivariable coupled and decentralized PID loops and has been successfully validated for a large number of experimental cases. PMID:12398277

  8. Computation of robustly stabilizing PID controllers for interval systems.

    PubMed

    Matušů, Radek; Prokop, Roman

    2016-01-01

    The paper is focused on the computation of all possible robustly stabilizing Proportional-Integral-Derivative (PID) controllers for plants with interval uncertainty. The main idea of the proposed method is based on Tan's (et al.) technique for calculation of (nominally) stabilizing PI and PID controllers or robustly stabilizing PI controllers by means of plotting the stability boundary locus in either P-I plane or P-I-D space. Refinement of the existing method by consideration of 16 segment plants instead of 16 Kharitonov plants provides an elegant and efficient tool for finding all robustly stabilizing PID controllers for an interval system. The validity and relatively effortless application of presented theoretical concepts are demonstrated through a computation and simulation example in which the uncertain mathematical model of an experimental oblique wing aircraft is robustly stabilized. PMID:27350931

  9. Recognizing Primary Immune Deficiency in Clinical Practice

    PubMed Central

    Yarmohammadi, Hale; Estrella, Lissette; Doucette, John; Cunningham-Rundles, Charlotte

    2006-01-01

    Primary immunodeficiency results in recurrent infections, organ dysfunction, and autoimmunity. We studied 237 patients referred for suspicion of immunodeficiency, using a scoring system based on clinical information. The 113 patients with immunodeficiency had higher scores and more episodes of chronic illnesses and were more likely to have neutropenia, lymphopenia, or splenomegaly. PMID:16522773

  10. Variable Structure PID Control to Prevent Integrator Windup

    NASA Technical Reports Server (NTRS)

    Hall, C. E.; Hodel, A. S.; Hung, J. Y.

    1999-01-01

    PID controllers are frequently used to control systems requiring zero steady-state error while maintaining requirements for settling time and robustness (gain/phase margins). PID controllers suffer significant loss of performance due to short-term integrator wind-up when used in systems with actuator saturation. We examine several existing and proposed methods for the prevention of integrator wind-up in both continuous and discrete time implementations.

  11. Design and tuning of robust PID controller for HVAC systems

    SciTech Connect

    Kasahara, Masato; Matsuba, Tadahiko; Kuzuu, Yoshiaki; Yamazaki, Takanori; Hashimoto, Yukihiro; Kamimura, Kazuyuki; Kurosu, Shigeru

    1999-07-01

    This paper concerns the development of a new design and tuning method for use with robust proportional-plus-integral-plus-derivative (PID) controllers that are commonly used in the heating, ventilating, and air-conditioning (HVAC) fields. The robust PID controller is designed for temperature control of a single-zone environmental space. Although the dynamics of environmental space are described by higher-order transfer functions, most HVAC plants are approximated by first-order lag plus deadtime systems. Its control performance is examined for this commonly approximated controlled plant. Since most HVAC plants are complex with nonlinearity, distributed parameters, and multivariables, a single set of PID gains does not necessarily yield a satisfactory control performance. For this reason, the PID controller must be designed as a robust control system considering model uncertainty caused by changes in characteristics of the plant. The PID gains obtained by solving a two-disk type of mixed sensitivity problem can be modified by contrast to those tuned by the traditional Ziegler-Nichols rule. The results, which are surprisingly simple, are given as linear functions of ratio of deadtime to time constant for robustness. The numerical simulation and the experiments on a commercial-size test plant for air conditioning suggest that the robust PID controller proposed in this paper is effective enough for practical applications.

  12. Staging Primary CNS Lymphoma

    MedlinePlus

    ... large vein near the heart. Having a weakened immune system may increase the risk of developing primary CNS ... immunodeficiency syndrome (AIDS) or other disorders of the immune system or who have had a kidney transplant . For ...

  13. Gene therapy for primary immunodeficiencies: Part 1.

    PubMed

    Cavazzana-Calvo, Marina; Fischer, Alain; Hacein-Bey-Abina, Salima; Aiuti, Alessandro

    2012-10-01

    Over 60 patients affected by SCID due to IL2RG deficiency (SCID-X1) or adenosine deaminase (ADA)-SCID have received hematopoietic stem cell gene therapy in the past 15 years using gammaretroviral vectors, resulting in immune reconstitution and clinical benefit in the majority of them. However, the occurrence of insertional oncogenesis in the SCID-X1 trials has led to the development of new clinical trials based on integrating vectors with improved safety design as well as investigation on new technologies for highly efficient gene targeting and site-specific gene editing. Here we will present the experience and perspectives of gene therapy for SCID-X1 and ADA-SCID and discuss the pros and cons of gene therapy in comparison to allogeneic transplantation. PMID:22981681

  14. AIDS: acquired immunodeficiency syndrome *

    PubMed Central

    Gilmore, N.J.; Beaulieu, R.; Steben, M.; Laverdière, M.

    1992-01-01

    Acquired immunodeficiency syndrome, or AIDS, is a new illness that occurs in previously healthy individuals. It is characterized by immunodeficiency, opportunistic infections and unusual malignant diseases. Life-threatening single or multiple infections with viruses, mycobacteria, fungi or protozoa are common. A rare neoplasm, Kaposi's sarcoma, has developed in approximately one third of patients with AIDS. More than 800 cases of AIDS have been reported in North America, over 24 of them in Canada. The majority of patients are male homosexuals, although AIDS has also developed in abusers of intravenously administered drugs, Haitian immigrants, individuals with hemophilia, recipients of blood transfusions, prostitutes, and infants, spouses and partners of patients with AIDS. The cause of AIDS is unknown, but the features are consistent with an infectious process. Early diagnosis can be difficult owing to the nonspecific symptoms and signs of the infections and malignant diseases. Therefore, vigilance by physicians is of the utmost importance. PMID:1544049

  15. Noninfectious Granulomas: A Sign of an Underlying Immunodeficiency?

    PubMed

    Shoimer, Ilya; Wright, Nicola; Haber, Richard M

    2016-05-01

    Primary immunodeficiency disorders, such as ataxia-telangiectasia (A-T), may rarely be associated with cutaneous granulomas without an identifiable infection. The authors report a case of a 3-year-old boy with A-T who presented with two persistent ulcerated erythematous nodules. Histopathology was consistent with a granulomatous process secondary to A-T, without an infectious origin. Partial improvement was noted with clobetasol propionate 0.05% cream applied twice daily under occlusion. Of note, the presence of multiple noninfectious granulomas in a child may be the initial sign of an immune deficiency and should alert the astute clinician to investigate for an underlying primary immunodeficiency. Herein, the authors discuss the associations of noninfectious granulomas and primary immunodeficiency disorders and present management options for these difficult-to-treat lesions. PMID:26728658

  16. Novel intelligent PID control of traveling wave ultrasonic motor.

    PubMed

    Jingzhuo, Shi; Yu, Liu; Jingtao, Huang; Meiyu, Xu; Juwei, Zhang; Lei, Zhang

    2014-09-01

    A simple control strategy with acceptable control performance can be a good choice for the mass production of ultrasonic motor control system. In this paper, through the theoretic and experimental analyses of typical control process, a simpler intelligent PID speed control strategy of TWUM is proposed, involving only two expert rules to adjust the PID control parameters based on the current status. Compared with the traditional PID controller, this design requires less calculation and more cheap chips which can be easily involved in online performance. Experiments with different load torques and voltage amplitudes show that the proposed controller can deal with the nonlinearity and load disturbance to maintain good control performance of TWUM. PMID:24957274

  17. ToA Coordinate Calculation Method Using a PID Algorithm

    NASA Astrophysics Data System (ADS)

    Hwang, Jae Ho; Kim, Jae Moung

    This paper introduces a coordinate calculation method for a real-time locating system. A ToA algorithm is used to obtain the target node coordinates, but a conventional DC method, which incurs heavy calculation time, is not suitable for embedded systems. This paper proposes the use of a P-control in the PID control algorithm to resolve real-time locating system issues. Performance measures of the accumulated operator number and position error are evaluated. It is shown that the PID method has less calculation and more robust performance than the DC method.

  18. Immunodeficiency and Autoimmune Enterocolopathy Linked to NFAT5 Haploinsufficiency

    PubMed Central

    Boland, Brigid S.; Widjaja, Christella E.; Banno, Asoka; Zhang, Bing; Kim, Stephanie H.; Stoven, Samantha; Peterson, Michael R.; Jones, Marilyn C.; Su, H. Irene; Crowe, Sheila E.; Bui, Jack D.; Ho, Samuel B.; Okugawa, Yoshinaga; Goel, Ajay; Marietta, Eric V.; Khosroheidari, Mahdieh; Jepsen, Kristen L.; Aramburu, Jose; Lopez-Rodriguez, Cristina; Sandborn, William J.; Murray, Joseph A.; Harismendy, Olivier; Chang, John T.

    2015-01-01

    The link between autoimmune diseases and primary immunodeficiency syndromes has been increasingly appreciated. Immunologic evaluation of a young man with autoimmune enterocolopathy and unexplained infections revealed evidence of immunodeficiency, including IgG subclass deficiency, impaired antigen-induced lymphocyte proliferation, reduced cytokine production by CD8+ T lymphocytes, and decreased numbers of natural killer (NK) cells. Genetic evaluation identified haploinsufficiency of NFAT5, a transcription factor regulating immune cell function and cellular adaptation to hyperosmotic stress, as a possible cause of this syndrome. Inhibition or deletion of NFAT5 in normal human and murine cells recapitulated several of the immune deficits identified in the patient. These results provide evidence of a primary immunodeficiency disorder associated with organ-specific autoimmunity linked to NFAT5 deficiency. PMID:25667416

  19. Space Flight Immunodeficiency

    NASA Technical Reports Server (NTRS)

    Shearer, William T.

    1999-01-01

    The National Aeronautics and Space Administration (NASA) has had sufficient concern for the well-being of astronauts traveling in space to create the National Space Biomedical Research Institute (NSBRI), which is investigating several areas of biomedical research including those of immunology. As part of the Immunology, Infection, and Hematology Team, the co-investigators of the Space Flight Immunodeficiency Project began their research projects on April 1, 1998 and are now just into the second year of work. Two areas of research have been targeted: 1) specific immune (especially antibody) responses and 2) non-specific inflammation and adhesion. More precise knowledge of these two areas of research will help elucidate the potential harmful effects of space travel on the immune system, possibly sufficient to create a secondary state of immunodeficiency in astronauts. The results of these experiments are likely to lead to the delineation of functional alterations in antigen presentation, specific immune memory, cytokine regulation of immune responses, cell to cell interactions, and cell to endothelium interactions.

  20. Comparative analysis of PSO algorithms for PID controller tuning

    NASA Astrophysics Data System (ADS)

    Štimac, Goranka; Braut, Sanjin; Žigulić, Roberto

    2014-09-01

    The active magnetic bearing(AMB) suspends the rotating shaft and maintains it in levitated position by applying controlled electromagnetic forces on the rotor in radial and axial directions. Although the development of various control methods is rapid, PID control strategy is still the most widely used control strategy in many applications, including AMBs. In order to tune PID controller, a particle swarm optimization(PSO) method is applied. Therefore, a comparative analysis of particle swarm optimization(PSO) algorithms is carried out, where two PSO algorithms, namely (1) PSO with linearly decreasing inertia weight(LDW-PSO), and (2) PSO algorithm with constriction factor approach(CFA-PSO), are independently tested for different PID structures. The computer simulations are carried out with the aim of minimizing the objective function defined as the integral of time multiplied by the absolute value of error(ITAE). In order to validate the performance of the analyzed PSO algorithms, one-axis and two-axis radial rotor/active magnetic bearing systems are examined. The results show that PSO algorithms are effective and easily implemented methods, providing stable convergence and good computational efficiency of different PID structures for the rotor/AMB systems. Moreover, the PSO algorithms prove to be easily used for controller tuning in case of both SISO and MIMO system, which consider the system delay and the interference among the horizontal and vertical rotor axes.

  1. Design of a PID Controller for a PCR Micro Reactor

    ERIC Educational Resources Information Center

    Dinca, M. P.; Gheorghe, M.; Galvin, P.

    2009-01-01

    Proportional-integral-derivative (PID) controllers are widely used in process control, and consequently they are described in most of the textbooks on automatic control. However, rather than presenting the overall design process, the examples given in such textbooks are intended to illuminate specific focused aspects of selection, tuning and…

  2. Advanced PID type fuzzy logic power system stabilizer

    SciTech Connect

    Hiyama, Takashi; Kugimiya, Masahiko; Satoh, Hironori . Dept. of Electrical Engineering and Computer Science)

    1994-09-01

    An advanced fuzzy logic control scheme has been proposed for a micro-computer based power system stabilizer to enhance the overall stability of power systems. The proposed control scheme utilizes the PID information of the generator speed. The input signal to the stabilizer is the real power output of a study unit. Simulations show the effectiveness of the advanced fuzzy logic control scheme.

  3. A new method for total OH reactivity measurements using a fast Gas Chromatographic Photo-Ionization Detector (GC-PID)

    NASA Astrophysics Data System (ADS)

    Nölscher, A. C.; Sinha, V.; Bockisch, S.; Klüpfel, T.; Williams, J.

    2012-05-01

    The primary and most important oxidant in the atmosphere is the hydroxyl radical (OH). Currently OH sinks, particularly gas phase reactions, are poorly constrained. One way to characterize the overall sink of OH is to measure directly the ambient loss rate of OH, the total OH reactivity. To date direct measurements of total OH reactivity have been either performed using a Laser Induced Fluorescence (LIF) system ("pump-and-probe" or "flow reactor") or the Comparative Reactivity Method (CRM) with a Proton Transfer Reaction Mass Spectrometer (PTR-MS). Both techniques require large, complex and expensive detection systems. This study presents a feasibility assessment for CRM total OH reactivity measurements using a new detector, a Gas Chromatographic Photo-Ionization Detector (GC-PID). Such a system is smaller, more portable, less power consuming and less expensive than other total OH reactivity measurement techniques. Total OH reactivity is measured by the CRM using a competitive reaction between a reagent (here pyrrole) with OH alone and in the presence of atmospheric reactive molecules. The new CRM method for total OH reactivity has been tested with parallel measurements of the GC-PID and the previously validated PTR-MS as detector for the reagent pyrrole during laboratory experiments, plant chamber and boreal field studies. Excellent agreement of both detectors was found when the GC-PID was operated under optimum conditions. Time resolution (60-70 s), sensitivity (LOD 3-6 s-1) and overall uncertainty (25% in optimum conditions) for total OH reactivity were equivalent to PTR-MS based total OH reactivity measurements. One drawback of the GC-PID system was the steady loss of sensitivity and accuracy during intensive measurements lasting several weeks, and a possible toluene interference. Generally, the GC-PID system has been shown to produce closely comparable results to the PTR-MS and thus in suitable environments (e.g. forests) it presents a viably economical

  4. Total OH reactivity measurements using a new fast Gas Chromatographic Photo-Ionization Detector (GC-PID)

    NASA Astrophysics Data System (ADS)

    Nölscher, A. C.; Sinha, V.; Bockisch, S.; Klüpfel, T.; Williams, J.

    2012-12-01

    The primary and most important oxidant in the atmosphere is the hydroxyl radical (OH). Currently OH sinks, particularly gas phase reactions, are poorly constrained. One way to characterize the overall sink of OH is to measure directly the ambient loss rate of OH, the total OH reactivity. To date, direct measurements of total OH reactivity have been either performed using a Laser-Induced Fluorescence (LIF) system ("pump-and-probe" or "flow reactor") or the Comparative Reactivity Method (CRM) with a Proton-Transfer-Reaction Mass Spectrometer (PTR-MS). Both techniques require large, complex and expensive detection systems. This study presents a feasibility assessment for CRM total OH reactivity measurements using a new detector, a Gas Chromatographic Photoionization Detector (GC-PID). Such a system is smaller, more portable, less power consuming and less expensive than other total OH reactivity measurement techniques. Total OH reactivity is measured by the CRM using a competitive reaction between a reagent (here pyrrole) with OH alone and in the presence of atmospheric reactive molecules. The new CRM method for total OH reactivity has been tested with parallel measurements of the GC-PID and the previously validated PTR-MS as detector for the reagent pyrrole during laboratory experiments, plant chamber and boreal field studies. Excellent agreement of both detectors was found when the GC-PID was operated under optimum conditions. Time resolution (60-70 s), sensitivity (LOD 3-6 s-1) and overall uncertainty (25% in optimum conditions) for total OH reactivity were similar to PTR-MS based total OH reactivity measurements. One drawback of the GC-PID system was the steady loss of sensitivity and accuracy during intensive measurements lasting several weeks, and a possible toluene interference. Generally, the GC-PID system has been shown to produce closely comparable results to the PTR-MS and thus in suitable environments (e.g. forests) it presents a viably economical

  5. Human immunodeficiency virus endocrinopathy

    PubMed Central

    Sinha, Uma; Sengupta, Nilanjan; Mukhopadhyay, Prasanta; Roy, Keshab Sinha

    2011-01-01

    Human immunodeficiency virus (HIV) endocrinopathy encompasses a broad spectrum of disorders. Almost all the endocrine organs are virtually affected by HIV infection. HIV can directly alter glandular function. More commonly secondary endocrine dysfunction occurs due to opportunistic infections and neoplasms in immunocompromised state. The complex interaction between HIV infection and endocrine system may be manifested as subtle biochemical and hormonal perturbation to overt glandular failure. Antiretroviral therapy as well as other essential medications often result in adverse endocrinal consequences. Apart from adrenal insufficiency, hypogonadism, diabetes and bone loss, AIDS wasting syndrome and HIV lipodystrophy need special reference. Endocrinal evaluation should proceed as in other patients with suspected endocrine dysfunction. Available treatment options have been shown to improve quality of life and long-term mortality in AIDS patients. PMID:22028995

  6. Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency.

    PubMed

    Lee, Wen-I; Huang, Jing-Long; Chen, Chien-Chang; Lin, Ju-Li; Wu, Ren-Chin; Jaing, Tang-Her; Ou, Liang-Shiou

    2016-03-01

    Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare, autosomal recessive and severe bowel disorder mainly caused by mutations in the tetratricopeptide repeat domain 37 (TTC37) gene which act as heterotetrameric cofactors to enhance aberrant mRNAs decay. The phenotype and immune profiles of SD/THE overlap those of primary immunodeficiency diseases (PIDs). Neonates with intractable diarrhea underwent immunologic assessments including immunoglobulin levels, lymphocyte subsets, lymphocyte proliferation, superoxide production, and IL-10 signaling function. Candidate genes for PIDs predisposing to inflammatory bowel disease were sequencing in this study. Two neonates, born to nonconsanguineous parents, suffered from intractable diarrhea, recurrent infections, and massive hematemesis from esopharyngeal varices due to liver cirrhosis or accompanying Trichorrhexis nodosa that developed with age and thus guided the diagnosis of SD/THE compatible to TTC37 mutations (homozygous DelK1155H, Fs*2; heterozygous Y1169Ter and InsA1143, Fs*3). Their immunologic evaluation showed normal mitogen-stimulated lymphocyte proliferation, superoxide production, and IL-10 signaling, but low IgG levels, undetectable antibody to hepatitis B surface antigen and decreased antigen-stimulated lymphocyte proliferation. A PubMed search for bi-allelic TTC37 mutations and phenotypes were recorded in 14 Asian and 12 non-Asian cases. They had similar presentations of infantile onset refractory diarrhea, facial dysmorphism, hair anomalies, low IgG, low birth weight, and consanguinity. A higher incidence of heart anomalies (8/14 vs 2/12; P = 0.0344, Chi-square), nonsense mutations (19 in 28 alleles), and hot-spot mutations (W936Ter, 2779-2G>A, and Y1169Ter) were found in the Asian compared with the non-Asian patients. Despite immunoglobulin therapy in 20 of the patients, 4 died from liver cirrhosis and 1 died from sepsis. Patients of all ethnicities with SD/THE with the characteristic

  7. Diagnosis of severe combined immunodeficiency

    PubMed Central

    Gennery, A; Cant, A

    2001-01-01

    Early diagnosis of severe combined immunodeficiency (SCID) is important to enable prompt referral to a supraregional centre for bone marrow transplantation before the occurrence of end organ damage secondary to infective complications. This review outlines clinical, microbiological, and immunopathological clues that aid the diagnosis of SCID and emphasises the multidisciplinary approach needed to diagnose and treat these infants. Key Words: severe combined immunodeficiency • bone marrow transplantation • adenosine deaminase deficiency PMID:11253129

  8. Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy.

    PubMed

    Kaveri, S V; Maddur, M S; Hegde, P; Lacroix-Desmazes, S; Bayry, J

    2011-06-01

    Intravenous immunoglobulin (IVIG) is a therapeutic compound prepared from pools of plasma obtained from several thousand healthy blood donors. For more than 20 years, IVIG has been used in the treatment of a wide range of primary and secondary immunodeficiencies. IVIG now represents a standard therapeutic option for most antibody deficiencies. Routinely, IVIG is used in patients with X-linked agammaglobulinaemia (XLA), common variable immunodeficiency (CVID), X-linked hyper-IgM, severe combined immunodeficiency, Wiskott-Aldrich syndrome, and selective IgG class deficiency. In addition, IVIG is used extensively in the treatment of a wide variety of autoimmune disorders. IVIG is administered at distinct doses in the two clinical settings: whereas immunodeficient patients are treated with replacement levels of IVIG, patients with autoimmune and inflammatory diseases are administered with very high doses of IVIG. Several lines of experimental evidence gathered in the recent years suggest that the therapeutic beneficial effect of IVIG in immunodeficiencies reflects an active role for IVIG, rather than a mere passive transfer of antibodies. PMID:21466545

  9. A Rare Case of Flare-Up of PID in Infertility Treatment

    PubMed Central

    Wadhwa, Leena; Wadhwa, Sanjana N.; Jindal, Sunita

    2015-01-01

    Case Presentation. Mrs. X, 35 years old, case of primary infertility, was diagnosed to have genital tuberculosis on the basis of PCR positive and hysterolaparoscopy findings and received category I ATT for 6 months. Following ATT completion, her USG revealed no evidence of tuboovarian mass or hydrosalpinx. Since her tubes were patent, she underwent 3 cycles of ovulation induction and 2 cycles of IUI. The women presented with acute PID, five days after IUI, and was conservatively managed. She again presented 24 days after IUI with persistent low grade fever and abdominal pain. Suspecting relapse of genital tuberculosis, she was started on category II ATT. She had acute episodes of high grade fever with chills 2 weeks after starting ATT and MRI revealed bilateral TO masses suggestive of pyosalpinx. Emergency laparotomy was done, pus was drained, and cyst wall was removed and HPE was suggestive of chronic inflammation with few granulation tissues. ATT was continued for one year and the woman improved. Conclusion. The possibility of flare-up of PID (pelvic inflammatory disease) in treated case of tuberculosis undergoing infertility management should be kept in mind and aggressive management should be done. PMID:26600959

  10. A Rare Case of Flare-Up of PID in Infertility Treatment.

    PubMed

    Wadhwa, Leena; Wadhwa, Sanjana N; Jindal, Sunita

    2015-01-01

    Case Presentation. Mrs. X, 35 years old, case of primary infertility, was diagnosed to have genital tuberculosis on the basis of PCR positive and hysterolaparoscopy findings and received category I ATT for 6 months. Following ATT completion, her USG revealed no evidence of tuboovarian mass or hydrosalpinx. Since her tubes were patent, she underwent 3 cycles of ovulation induction and 2 cycles of IUI. The women presented with acute PID, five days after IUI, and was conservatively managed. She again presented 24 days after IUI with persistent low grade fever and abdominal pain. Suspecting relapse of genital tuberculosis, she was started on category II ATT. She had acute episodes of high grade fever with chills 2 weeks after starting ATT and MRI revealed bilateral TO masses suggestive of pyosalpinx. Emergency laparotomy was done, pus was drained, and cyst wall was removed and HPE was suggestive of chronic inflammation with few granulation tissues. ATT was continued for one year and the woman improved. Conclusion. The possibility of flare-up of PID (pelvic inflammatory disease) in treated case of tuberculosis undergoing infertility management should be kept in mind and aggressive management should be done. PMID:26600959

  11. Tuning of PID controllers for boiler-turbine units.

    PubMed

    Tan, Wen; Liu, Jizhen; Fang, Fang; Chen, Yanqiao

    2004-10-01

    A simple two-by-two model for a boiler-turbine unit is demonstrated in this paper. The model can capture the essential dynamics of a unit. The design of a coordinated controller is discussed based on this model. A PID control structure is derived, and a tuning procedure is proposed. The examples show that the method is easy to apply and can achieve acceptable performance. PMID:15535395

  12. Optimal Pid Controller Design Using Adaptive Vurpso Algorithm

    NASA Astrophysics Data System (ADS)

    Zirkohi, Majid Moradi

    2015-04-01

    The purpose of this paper is to improve theVelocity Update Relaxation Particle Swarm Optimization algorithm (VURPSO). The improved algorithm is called Adaptive VURPSO (AVURPSO) algorithm. Then, an optimal design of a Proportional-Integral-Derivative (PID) controller is obtained using the AVURPSO algorithm. An adaptive momentum factor is used to regulate a trade-off between the global and the local exploration abilities in the proposed algorithm. This operation helps the system to reach the optimal solution quickly and saves the computation time. Comparisons on the optimal PID controller design confirm the superiority of AVURPSO algorithm to the optimization algorithms mentioned in this paper namely the VURPSO algorithm, the Ant Colony algorithm, and the conventional approach. Comparisons on the speed of convergence confirm that the proposed algorithm has a faster convergence in a less computation time to yield a global optimum value. The proposed AVURPSO can be used in the diverse areas of optimization problems such as industrial planning, resource allocation, scheduling, decision making, pattern recognition and machine learning. The proposed AVURPSO algorithm is efficiently used to design an optimal PID controller.

  13. Design and implementation of a 2-DOF PID compensation for magnetic levitation systems.

    PubMed

    Ghosh, Arun; Rakesh Krishnan, T; Tejaswy, Pailla; Mandal, Abhisek; Pradhan, Jatin K; Ranasingh, Subhakant

    2014-07-01

    This paper employs a 2-DOF (degree of freedom) PID controller for compensating a physical magnetic levitation system. It is shown that because of having a feedforward gain in the proposed 2-DOF PID control, the transient performance of the compensated system can be changed in a desired manner unlike the conventional 1-DOF PID control. It is also shown that for a choice of PID parameters, although the theoretical loop robustness is the same for both the compensated systems, in real-time, 2-DOF PID control may provide superior robustness if a suitable choice of the feedforward parameter is made. The results are verified through simulations and experiments. PMID:24947430

  14. Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity.

    PubMed

    Lobachevsky, Pavel; Woodbine, Lisa; Hsiao, Kuang-Chih; Choo, Sharon; Fraser, Chris; Gray, Paul; Smith, Jai; Best, Nickala; Munforte, Laura; Korneeva, Elena; Martin, Roger F; Jeggo, Penny A; Martin, Olga A

    2015-09-01

    Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of γ histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects. PMID:26151233

  15. Evaluation of Severe Combined Immunodeficiency and Combined Immunodeficiency Pediatric Patients on the Basis of Cellular Radiosensitivity

    PubMed Central

    Lobachevsky, Pavel; Woodbine, Lisa; Hsiao, Kuang-Chih; Choo, Sharon; Fraser, Chris; Gray, Paul; Smith, Jai; Best, Nickala; Munforte, Laura; Korneeva, Elena; Martin, Roger F.; Jeggo, Penny A.; Martin, Olga A.

    2016-01-01

    Pediatric patients with severe or nonsevere combined immunodeficiency have increased susceptibility to severe, life-threatening infections and, without hematopoietic stem cell transplantation, may fail to thrive. A subset of these patients have the radiosensitive (RS) phenotype, which may necessitate conditioning before hematopoietic stem cell transplantation, and this conditioning includes radiomimetic drugs, which may significantly affect treatment response. To provide statistical criteria for classifying cellular response to ionizing radiation as the measure of functional RS screening, we analyzed the repair capacity and survival of ex vivo irradiated primary skin fibroblasts from five dysmorphic and/or developmentally delayed pediatric patients with severe combined immunodeficiency and combined immunodeficiency. We developed a mathematical framework for the analysis of γ histone 2A isoform X foci kinetics to quantitate DNA-repair capacity, thus establishing crucial criteria for identifying RS. The results, presented in a diagram showing each patient as a point in a 2D RS map, were in agreement with findings from the assessment of cellular RS by clonogenic survival and from the genetic analysis of factors involved in the nonhomologous end-joining repair pathway. We provide recommendations for incorporating into clinical practice the functional assays and genetic analysis used for establishing RS status before conditioning. This knowledge would enable the selection of the most appropriate treatment regimen, reducing the risk for severe therapy-related adverse effects. PMID:26151233

  16. PID: from material properties to outdoor performance and quality control counter measures

    NASA Astrophysics Data System (ADS)

    Berghold, J.; Koch, S.; Pingel, S.; Janke, S.; Ukar, A.; Grunow, P.; Shioda, T.

    2015-09-01

    Although the main root causes and referring counter measures for PID are known, a significant part of the industrial modules are still found to be PID sensitive in testing and PID is increasingly evident in field. This paper discusses field occurrence of PID with respect to environmental conditions and material properties. Different PID pattern in field and in test are analyzed in terms of the potential distribution and surface conductivity. Examples are given for the correlation of PID lab tests of a (commercial) BOM with real outdoor degradation. PID progress is predicted for different locations and compared with measurement data. Suitable quality control measures are discussed for the modules as well as for the encapsulation material

  17. Neural PID Control of Robot Manipulators With Application to an Upper Limb Exoskeleton.

    PubMed

    Yu, Wen; Rosen, Jacob

    2013-04-01

    In order to minimize steady-state error with respect to uncertainties in robot control, proportional-integral-derivative (PID) control needs a big integral gain, or a neural compensator is added to the classical proportional-derivative (PD) control with a large derivative gain. Both of them deteriorate transient performances of the robot control. In this paper, we extend the popular neural PD control into neural PID control. This novel control is a natural combination of industrial linear PID control and neural compensation. The main contributions of this paper are semiglobal asymptotic stability of the neural PID control and local asymptotic stability of the neural PID control with a velocity observer which are proved with standard weight training algorithms. These conditions give explicit selection methods for the gains of the linear PID control. An experimental study on an upper limb exoskeleton with this neural PID control is addressed. PMID:23033432

  18. Immunodeficiency in Patients With 49,XXXXY Chromosomal Variation

    PubMed Central

    Keller, Michael D.; Sadeghin, Teresa; Samango-Sprouse, Carole; Orange, Jordan S.

    2016-01-01

    Boys affected with 49,XXXXY sex chromosomal variation have been described to have high incidence of recurrent otitis media and asthma, the cause of which is unknown. We hypothesized that primary immunodeficiency occurs in patients with XXXXY aneuploidy. To investigate this, 31 boys with known 49,XXXXY were evaluated through a multidisciplinary clinic. Screening history was performed using the “10 Warning Signs of primary immunodeficiency” (Jeffrey Modell Foundation), as well as by history of atopic and autoimmune conditions. Of the 31 boys, 20 had at least two warning signs of primary immunodeficiency, and five had four or more signs. Sixteen had history of recurrent pneumonia, and 15 carried the diagnosis of asthma. Of the 10 who underwent immunologic screening, eight showed some evidence of impaired antibody responses to polysaccharide antigens, and one was diagnosed with specific antibody deficiency. These preliminary results suggest a high incidence of both atopy and antibody deficiency in boys with 49,XXXXY. PMID:23345259

  19. An Attitude Control of Flexible Spacecraft Using Fuzzy-PID Controller

    NASA Astrophysics Data System (ADS)

    Park, Jong-Oh; Im, Young-Do

    This primary objective of this study is to demonstrate simulation and ground-based experiment for the attitude control of flexible spacecraft. A typical spacecraft structure consists of the rigid body and flexible appendages which are large flexible solar panels, parabolic antennas built from light materials in order to reduce their weight. Therefore the attitude control has a big problem because these appendages induce structural vibration under the excitation of external forces. A single-axis rotational simulator with a flexible arm is constructed with on-off air thrusters and reaction wheel as actuation. The simulator is also equipped with payload pointing capability by simultaneous thruster and DC servo motor actuation. The experiment of flexible spacecraft attitude control is performed using only the reaction wheel. Using the reaction wheel the performance of the fuzzy-PID controller is illustrated by simulation and experimental results for a single-axis rotational simulator.

  20. Human immunodeficiency virus infection and pneumothorax

    PubMed Central

    Terzi, Eirini; Zarogoulidis, Konstantinos; Kougioumtzi, Ioanna; Dryllis, Georgios; Kioumis, Ioannis; Pitsiou, Georgia; Machairiotis, Nikolaos; Katsikogiannis, Nikolaos; Tsiouda, Theodora; Madesis, Athanasios; Karaiskos, Theodoros

    2014-01-01

    Pneumothorax is a serious and relatively frequent complication of human immunodeficiency virus (HIV) infection that may associate with increased morbidity and mortality and may prove difficult to manage, especially in patients with acquired immunodeficiency syndrome (AIDS). PMID:25337392

  1. Chronic Giardiasis in a Case of Common Variable Immunodeficiency (CVID): A Case Report

    PubMed Central

    Koticha, Avani; Mehta, Preeti R

    2016-01-01

    Common Variable Immunodeficiency (CVID) is a primary immunodeficiency characterized by low antibody levels and recurrent infections. This makes an individual more prone to recurrent respiratory and gastrointestinal tract infections. In cases where there is persistent positive finding of intestinal parasites in stool, a high index of suspicion should be raised to rule out immunodeficiency state. Early diagnosis of such cases will help in reducing the morbidity and better management of the patient. A case of CVID in 18-year-old male with recurrent lower respiratory tract infection and chronic diarrhoea due to Giardia lamblia is reported herewith.

  2. PID Gain Tuning for Disturbance Attenuation FRIT Method

    NASA Astrophysics Data System (ADS)

    Masuda, Shiro

    This review paper shows a PID gains tuning method from one-shot experimental data generated by test signal added at input signal in an off-line manner, so that the output signal could follow the prescribed reference model output. We call the method a “disturbance attenuation FRIT method” because the test signal added at input signal is a benchmark signal evaluating disturbance attenuation property. The experimental result for helicopter attitude control model is demonstrated to show the effectiveness of the disturbance attenuation FRIT method.

  3. Progress on Development of the New FDIRC PID Detector

    SciTech Connect

    Vavra, Jerry

    2012-08-03

    We present a progress status of a new concept of PID detector called FDIRC, intended to be used at the SuperB experiment, which requires {pi}/K separation up to a few GeV/c. The new photon camera is made of the solid fused-silica optics with a volume 25x smaller and speed increased by a factor of ten compared to the BaBar DIRC, and therefore will be much less sensitive to electromagnetic and neutron background

  4. Feline immunodeficiency virus infection.

    PubMed

    Pedersen, N C; Yamamoto, J K; Ishida, T; Hansen, H

    1989-05-01

    Feline immunodeficiency virus (FIV) (formerly feline T-lymphotropic lentivirus or FTLV) was first isolated from a group of cats in Petaluma, California in 1986. The virus is a typical lentivirus in gross and structural morphology. It replicates preferentially but not exclusively in feline T-lymphoblastoid cells, where it causes a characteristic cytopathic effect. The major structural proteins are 10, 17 (small gag), 28 (major core), 31 (endonuclease?), 41 (transmembrane?), 52 (core precursor polyprotein), 54/62 (reverse transcriptase?), and 110/130 (major envelope) kilodaltons in size. The various proteins are antigenically distinguishable from those of other lentiviruses, although serum from EIAV-infected horses will cross-react with some FIV antigens. Kittens experimentally infected with FIV manifest a transient (several days to 2 weeks) fever and neutropenia beginning 4 to 8 weeks after inoculation. This is associated with a generalized lymphadenopathy that persists for up to 9 months. Most cats recover from this initial phase of the disease and become lifelong carriers of the virus. Complete recovery does not occur to any extent in nature or in the laboratory setting. One experimentally infected cat died from a myeloproliferative disorder several months after infection. The terminal AIDS-like phase of the illness has been seen mainly in naturally infected cats. It appears a year or more following the initial infection in an unknown proportion of infected animals. FIV has been identified in cats from all parts of the world. It is most prevalent in high density populations of free roaming cats (feral and pet), and is very uncommon in closed purebred catteries. Male cats are twice as likely to become infected as females. Older male cats adopted as feral or stray animals are at the highest risk of infection, therefore. The infection rate among freely roaming cats rises throughout life, and reaches levels ranging from less than 1% to 12% or more depending on the

  5. Ocular examination and diagnosis in patients with the acquired immunodeficiency syndrome.

    PubMed Central

    Gariano, R F; Rickman, L S; Freeman, W R

    1993-01-01

    Ocular involvement is seen frequently and is an important source of morbidity in patients with the acquired immunodeficiency syndrome. We outline here the general skills of physical diagnosis valuable to primary care physicians or infectious diseases specialists in recognizing and evaluating ocular complaints in patients infected with the human immunodeficiency virus. We provide an overview of common ocular diseases in these patients, with an emphasis on signs and symptoms that aid in the differential diagnosis. Images PMID:8384763

  6. Common Variable Immunodeficiency (CVID)

    MedlinePlus

    ... on ClinicalTrials.gov . Related Links Primary Immune Deficiency Diseases (PIDDs) Immune System National Library of Medicine, Genetics Home Reference ​​​​​ ... and an increased risk of infections. Although the disease usually is diagnosed in ... a defect in the capability of immune cells to produce normal amounts of all types ...

  7. Design of an Implicit GMV-PID Controller Using Closed Loop Data

    NASA Astrophysics Data System (ADS)

    Wakitani, Shin; Hosokawa, Kei; Yamamoto, Toru

    In industrial processes, PID control has been applied to a lot of real systems. The control performance strongly depends on PID parameters. Although, some schemes for tuning PID parameters have been proposed, however, these schemes need system parameters which are estimated by system identification in order to calculate PID parameters. On the other hand, model-free controller design schemes represented by VRFT or FRIT which have received much attention in last few years. These methods can calculate control parameters using closed-loop data and are expected to reduce computational costs. In this paper, a type of implicit PID controllers using closed-loop data is proposed. According to the proposed method, PID parameters are calculated based on the implicit GMVC. Moreover, the control performance can be suitably adjusted by only user-specified parameter. The effectiveness of the proposed method is numerically and experimentally evaluated.

  8. Hybrid Takagi-Sugeno Fuzzy FED PID Control of Nonlinear Systems

    NASA Astrophysics Data System (ADS)

    Hamed, Basil; El Khateb, Ahmad

    2008-06-01

    The new method of proportional-integral-derivative (PID) controller is proposed in this paper for a hybrid fuzzy PID controller for nonlinear system. The important feature of the proposed approach is that it combines the fuzzy gain scheduling method and a fuzzy fed PID controller to solve the nonlinear control problem. The resultant fuzzy rule base of the proposed controller contains one part. This single part of the rules uses the Takagi-Sugeno method for solving the nonlinear problem. The simulation results of a nonlinear system show that the performance of a fed PID Hybrid Takagi-Sugeno fuzzy controller is better than that of the conventional fuzzy PID controller or Hybrid Mamdani fuzzy FED PID controller.

  9. PID1 (NYGGF4), a new growth-inhibitory gene in embryonal brain tumors and gliomas

    PubMed Central

    Erdreich-Epstein, Anat; Robison, Nathan; Ren, Xiuhai; Zhou, Hong; Xu, Jingying; Davidson, Tom B.; Schur, Mathew; Gilles, Floyd H.; Ji, Lingyun; Malvar, Jemily; Shackleford, Gregory M.; Margol, Ashley S.; Krieger, Mark D.; Judkins, Alexander R.; Jones, David T.W.; Pfister, Stefan; Kool, Marcel; Sposto, Richard; Asgharazadeh, Shahab

    2014-01-01

    Purpose We present here the first report of PID1 (Phosphotyrosine Interaction Domain containing 1; NYGGF4) in cancer. PID1 was identified in 2006 as a gene that modulates insulin signaling and mitochondrial function in adipocytes and muscle cells. Experimental Design and Results Using four independent medulloblastoma datasets, we show that mean PID1 mRNA levels were lower in unfavorable medulloblastomas (Groups 3 and 4, and anaplastic histology) compared with favorable medulloblastomas (SHH and WNT groups, and desmoplastic/nodular histology) and with fetal cerebellum. In two large independent glioma datasets PID1 mRNA was lower in glioblastomas (GBMs), the most malignant gliomas, compared to other astrocytomas, oligodendrogliomas and non-tumor brains. Neural and proneural GBM subtypes had higher PID1 mRNA compared to classical and mesenchymal GBM. Importantly, overall survival and radiation-free progression-free survival were longer in medulloblastoma patients with higher PID1 mRNA (univariate and multivariate analyses). Higher PID1 mRNA also correlated with longer overall survival in glioma and GBM patients. In cell culture, overexpression of PID1 inhibited colony formation in medulloblastoma, atypical teratoid rhabdoid tumor (ATRT) and GBM cell lines. Increasing PID1 also increased cell death and apoptosis, inhibited proliferation, induced mitochondrial depolarization, and decreased serum-mediated phosphorylation of AKT and ERK in medulloblastoma, ATRT and/or GBM cell lines, whereas siRNA to PID1 diminished mitochondrial depolarization. Conclusions These data are the first to link PID1 to cancer and suggest that PID1 may have a tumor inhibitory function in these pediatric and adult brain tumors. PMID:24300787

  10. Mutation particle swarm optimization of the BP-PID controller for piezoelectric ceramics

    NASA Astrophysics Data System (ADS)

    Zheng, Huaqing; Jiang, Minlan

    2016-01-01

    PID control is the most common used method in industrial control because its structure is simple and it is easy to implement. PID controller has good control effect, now it has been widely used. However, PID method has a few limitations. The overshoot of the PID controller is very big. The adjustment time is long. When the parameters of controlled plant are changing over time, the parameters of controller could hardly change automatically to adjust to changing environment. Thus, it can't meet the demand of control quality in the process of controlling piezoelectric ceramic. In order to effectively control the piezoelectric ceramic and improve the control accuracy, this paper replaced the learning algorithm of the BP with the mutation particle swarm optimization algorithm(MPSO) on the process of the parameters setting of BP-PID. That designed a better self-adaptive controller which is combing the BP neural network based on mutation particle swarm optimization with the conventional PID control theory. This combination is called the MPSO-BP-PID. In the mechanism of the MPSO, the mutation operation is carried out with the fitness variance and the global best fitness value as the standard. That can overcome the precocious of the PSO and strengthen its global search ability. As a result, the MPSO-BP-PID can complete controlling the controlled plant with higher speed and accuracy. Therefore, the MPSO-BP-PID is applied to the piezoelectric ceramic. It can effectively overcome the hysteresis, nonlinearity of the piezoelectric ceramic. In the experiment, compared with BP-PID and PSO-BP-PID, it proved that MPSO is effective and the MPSO-BP-PID has stronger adaptability and robustness.